2-Substituted-4-substituted-1,3-dioxolanes and use thereof

ABSTRACT

Nucleoside analogues containing a 1,3-dioxolane structure are suitable antiviral agents, particulary for the treatment of the HIV infections in mammals, especially humans. Examples of the nucleoside analogues include:cis-2-acetoxymethyl-4-(thymin-1&#39;-yl)-1,3,-dioxolane,cis-2-hydroxymethyl-4-(thymin-1&#39;-yl)-1,3-dioxolane,cis-2-benzoyloxymethyl-4-(cytosin-1&#39;-yl)-1,3-dioxolane, andcis-2-hydroxymethyl-4-(cytosin-1&#39;-yl)-1,3-dioxolane.These compounds can be in the form of their racemates or their separate enantiomers.

The instant application is a continuation of application Ser. No.08/306,830, filed Sep. 15, 1994, which is a continuation of Ser. No.07/564,160, now abandoned, filed Aug. 7, 1990, which in turn is acontinuation-in-part of Ser. No. 07/308,101, filed Feb. 8, 1989 (nowU.S. Pat. No. 5,047,407) and a continuation-in-part of Ser. No.07/546,676, filed Jun. 29, 1990 (now U.S. Pat. No. 5,041,449), and Ser.No. 07/546,676 is a continuation of Ser. No. 07/179,165, now abandoned,filed Apr. 11, 1988. Ser. No. 07/666,045, filed Mar. 7, 1991 (now U.S.Pat. No. 5,270,315) is a divisional of Ser. No. 07/546,676.

The present invention relates to novel substituted 1,3-oxathiolane andsubstituted-1,3-dioxolane cyclic compounds having pharmacologicalactivity, to processes for and intermediates of use in theirpreparation, to pharmaceutical compositions containing them, and to theuse of these compounds in the antiviral treatment of mammals.

Retroviral infections are a serious cause of disease, most notably, theacquired immunodeficiency syndrome (AIDS). The human immunodeficiencyvirus (HIV) has been recognized as the etiologic agent of AIDS, andcompounds having an inhibitory effect against HIV multiplication havebeen actively sought.

Mitsuya et al., “3′-Azido-3′-deoxythymidine (BW A509U): An antiviralagent that inhibits the infectivity and cytopathic effect of humanT-lympho-tropic virus type III/lymphadenopathy-associated virus invitro”, Proc. Natl. Acad. Sci. U.S.A., 82, pp. 7096-7100 (1985), refersto a compound of formula (A) (3′-azido-2′,3′-dideoxythymidine), commonlyreferred to as AZT. This compound is said to be useful in providing someprotection for AIDS carriers against the cytopathogenic effect ofimmunodeficiency virus (HIV).

Mitsuya et al., “Inhibition of the in vitro infectivity and cytopathiceffect of human T-lympho-trophic virus typeIII/lymphadenopathy-associated virus (HTLV-III/LAV) by2′3′-dideoxynucleosides”, Proc. Natl. Acad. Sci. U.S.A., 86, pp. 1911-15(1986), have also referred to a group of 2′,3′-dideoxynucleosides shownin formula (B) which are said to possess protective activity againstHIV-induced cytopathogenicity.

Balzarini et al., “Potent and selective anti-HTLV-III/LAV activity of2′,3′-dideoxycytidinene, the 2′,3′-unsaturated derivative of2′,3′-dideoxycytidine”, Biochem. Biophys. Res. Comm., 140, pp. 735-42(1986), refer to an unsaturated analogue of thesenucleosides—2′,3′-dideoxycytidine, shown in formula (C)—as beingcharacterized by antiretroviral activity.

Baba et al., “Both 2′,3′-dideoxythymidine and its 2′,3′-unsaturatedderivative (2′,3′-dideoxythymidine) are potent and selective inhibitorsof human immunodeficiency virus replication in vitro”, Biochem. Biophys.Res. Comm., 142, pp. 128-34 (1987), refer to the 2′,3′-unsaturatedanalogue shown in formula (D) of 2′,3′-dideoxythymidine. This analogueis purported to be a potent selective inhibitor of HIV replication.

Analogues of AZT known as 3′-azido-2′,3′-dideoxyuridine shown in formula(E), where Y is bromine or iodine, have been said to have an inhibitoryactivity against Moloney murine leukemia in T. S. Lin et al., “Synthesisand antiviral activity of various 3′-azido,3′ amino,2′,3′-unsaturatedand 2′,3′-dideoxy analogues of pyrimidine, deoxyribonucleosides againstretroviruses”, J. Med. Chem., 30, pp. 440-41 (1987).

Finally, the 3′-fluoro analogues of 2′,3′-dideoxythymidine shown informula (F) and of 2′,3′-dideoxythymidine shown in formula (G) arereferred to in Herdewijn et al., “3′-Substituted 2′,3′-dideoxynucleosideanalogues as potential anti-HIV(HTLV-III/LAV) agents”, J. Med. Chem.,30, pp. 1270-78 (1987), as having potent antiretroviral activity.

The most potent anti-HIV compounds thus far reported are2′,3′-dideoxynucleosides, more particularly, 2′,3′-dideoxy cytidine(ddCyd) and 3′-azido-2′,3′-dideoxythymidine (AzddThd or AZT). Thesecompounds are also active against other kinds of retroviruses such asthe Moloney murine leukemia virus. Because of the increasing incidenceand the life-threatening characteristics of AIDS, efforts are beingexpended to discover and develop new non-toxic and potent inhibitors ofHIV and blockers of its infectivity. It is therefore an object of thepresent invention to provide effective anti-HIV compounds of lowtoxicity and a synthesis of such new compounds that is readily feasible.

A structurally distinct class of compounds known as2-substituted-5-substituted-1,3-oxathiolanes and2-substituted-4-substituted-1,3-dioxolanes has now been discovered andfound to have antiretroviral activity. In particular, these compoundshave been found to act as non-toxic inhibitors of the replication ofHIV-1 in T-lymphocytes over prolonged periods of time.

There are accordingly provided in a first aspect of this inventioncompounds of formula (I)

wherein R₁ is hydrogen or an acyl radical from 1 to 16 carbon atoms,preferably a benzoyl or a benzoyl substituted in any position by atleast one halogen (bromine, chlorine, fluorine or iodine), C₁₋₆ alkyl,C₁₋₆ alkoxy, nitro or trifluoromethyl groups;

R₂ is a purine or pyrimidine base or an analogue or derivative thereof;

Z is O, S, S═O or SO₂; and

R₁ can be, for example, acetyl, hexanoyl, or aroyl.

The art that the compounds of formula (I) contain at least two chiralcenters (shown as * in formula (I)) and thus exist in the form of twopairs of optical isomers (i.e., enantiomers) and mixtures thereofincluding racemic mixtures. Thus the compounds of formula (I) may beeither cis isomers, as represented by formula (II), or trans isomers, asrepresented by formula (III), or mixtures thereof. Each of the cis andtrans isomers can exist as one of two enantiomers or as mixtures thereofincluding racemic mixtures. All such isomers and mixtures thereofincluding racemic mixtures are included within the scope of theinvention.

The compounds of formula (I) are preferably in the form of their cisisomers.

It will also be appreciated that when Z is S═O the compounds exist intwo additional isomeric forms as shown in formulas (IIa) and (IIb) whichdiffer in the configuration of the oxide oxygen atom relative to the2,5-substituents. The compounds of the invention additionally embracesuch isomers and mixtures thereof.

The purine or pyrimidine base or analogue or derivative thereof R₂ willbe linked at the 9- or 1-position, respectively.

By “purine or pyrimidine base” or an analogue or derivative thereof ismeant a purine or pyrimidine base found in native nucleosides or ananalogue thereof which mimics such bases in that their structures (thekinds of atoms and their arrangement) are similar to the native basesbut may either possess additional or lack certain of the functionalproperties of the native bases. Such analogues include those derived byreplacement of a CH₂ moiety by a nitrogen atom (for example,5-azapyrimidines such as 5-azacytosine) or vice verse (for example7-deazapurines, for example 7-deazadenosine or 7-deazaguanosine) or both(e.g., 7-deaza-8-azapurines). By derivatives of such bases or analoguesare meant those compounds wherein ring substituents are eitherincorporated, removed or modified by conventional substituents known inthe art, e.g., halogen, hydroxyl, amino, C₁₋₆ alkyl. Such purine orpyrimidine bases, analogues and derivatives will be well known to thoseskilled in the art.

Conveniently the group R₂ is selected from:

wherein R₃ is selected from the group of hydrogen, acetyl, hydroxyl orC₁₋₆ alkyl or alkenyl groups;

R₄ and R₅ are independently selected from the group of hydrogen,hydroxymethyl, trifluoromethyl, substituted or unsubstituted C₁₋₆ alkylor alkenyl groups, bromine, chlorine, fluorine, or iodine; R6 isselected from the group of hydrogen, cyano, carboxy, ethoxycarbonyl,carbamoyl, or thiocarbamoyl; and

X and Y are independently selected from the group of hydrogen, bromine,chlorine, fluorine, iodine, amino or hydroxy groups.

Preferably R₂ is

wherein R₃ and R₄ are as defined hereinabove.

Z is preferably —S—.

When the compound of formula (I) is a 1,3-oxathiolane of formula (Ia),where Z is S, S═O or SO₂,

preferably:

R₁ is selected from a group consisting of hydrogen and an acyl grouphaving 1 to 16 carbon atoms;

R₂ is a heterocyclic radical selected from the group consisting of:

 R₃ and R₄ are independently selected from the group consisting ofhydrogen and C₁₋₆ alkyl groups;

R₅ is selected from the group consisting of hydrogen, C₁₋₆ alkyl,bromine, chlorine, fluorine, and iodine; and

X and Y are independently selected from the group consisting of bromine,chlorine, fluorine, iodine, amino and hydroxyl groups.

When the compound of formula (I) is a 1,3-dioxolane of formula (Ib),

preferably:

R₁ is selected from the group consisting of hydrogen, an aliphatic acylgroup having 1 to 16 carbon atoms, benzoyl and benzoyl substituted inany position by a halogen, a lower alkyl, a lower alkoxy, a nitro or atrifluoromethyl group;

R₂ is a heterocyclic radical selected from the group consisting of:

wherein:

R₃ is selected from the group consisting of hydrogen and lower alkylradicals having from 1 to 3 carbon atoms;

R₄ is selected from the group consisting of hydrogen, lower alkyl andalkenyl radicals having from 1 to 3 carbon atoms; and

R₅ is selected from the group consisting of lower alkyl and alkenylradicals having from 1-3 carbon atoms, fluoro and iodo.

By “a pharmaceutically acceptable derivative” is meant anypharmaceutically acceptable salt, ester, or salt of such ester, of acompound of formula (I) or any other compound which, upon administrationto the recipient, is capable of providing (directly or indirectly) acompound of formula (I) or an antivirally active metabolite or residuethereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) may be modified to provide pharmaceutically acceptablederivatives thereof, at functional groups in both the base moiety, R₂,and at the hydroxymethyl group of the oxathiolane or dioxolane ring.Modification at all such functional groups is included within the scopeof the invention. However, of particular interest are pharmaceuticallyacceptable derivatives (e.g., esters) obtained by modification of the2-hydroxymethyl group of the oxathiolane or dioxolane ring.

Preferred esters of the compounds of formula (I) include the compoundsin which R₁ is replaced by a carboxyl function

in which the non-carbonyl moiety R of the ester grouping is selectedfrom hydrogen, straight or branched chain alkyl (e.g., methyl, ethyl,n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl(e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyloptionally substituted by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy);substituted dihydro pyridinyl (e.g., N-methyldihydro pyridinyl);sulphonate esters such as alkyl- or aralkylsulphonyl (e.g.,methanesulphonyl); sulfate esters; amino acid esters (e.g., L-valyl orL-isoleucyl) and mono-, di- or tri-phosphate esters.

Also included within the scope of such esters are esters derived frompolyfunctional acids such as carboxylic acids containing more than onecarboxyl group, for example, dicarboxylic acids HO₂C(CH₂)_(n)CO₂H wheren is an integer of 1 to 10 (for example, succinic acid) or phosphoricacids. Methods for preparing such esters are well known. See, forexample, Hahn et al., “Nucleotide Dimers as Anti-Human ImmunodeficiencyVirus Agents”, Nucleotide Analooues, pp. 156-159 (1989) and Busso etal., “Nucleotide Dimers Suppress HIV Expression In Vitro”, AIDS Researchand Human Retroviruses, 4(6), pp. 449-455 (1988). Where esters arederived from such acids, each acidic group is preferably esterified by acompound of formula (I) or other nucleosides or analogues andderivatives thereof to provide esters of the formula (IV) where:

W is

and n is an integer of 1 to 10 or

J is any nucleoside or nucleoside analog or derivative thereof and Z andR₂ are as defined above. Among the preferred nucleosides and nucleosideanalogues are 3′-azido-2′3′-dideoxy-thymidine, 2′,3′-dideoxycytidine,2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine, 2′,3′-dideoxythymidine,2′,3′-dideoxy-2′,3′-didehydrothymidine, and2′,3′-dideoxy-2′,3′-didehydrocytidine and ribavirin and thosenucleosides whose bases are depicted on pages 7-8 of this specification.We most prefer a homodimer consisting of two nucleosides of formula (I).

With regard to the above described esters, unless otherwise specified,any alkyl moiety present advantageously contains 1 to 16 carbon atoms,preferably 1 to 4 carbon atoms and could contain one or more doublebonds. Any aryl moiety present in such esters advantageously comprises aphenyl group.

In particular the esters may be a C₁₋₁₆ alkyl ester, an unsubstitutedbenzoyl ester or a benzoyl ester substituted by at least one halogen(bromine, chlorine, fluorine or iodine), C₁₋₆ alkyl or alkenyl,saturated or unsaturated C₁₋₆ alkoxy, nitro or trifluoromethyl groups.

Pharmaceutically acceptable salts of the compounds of formula (1)include those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.Other acids such as oxalic, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium and NR₄+(where R is C₁₋₄ alkyl) salts.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptablederivatives.

Specific compounds of formula (I) include:

Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane,trans-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, and mixturesthereof;

Cis-2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane,trans-2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane, and mixturesthereof;

Cis-2-hydroxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-1,3-oxathiolane,trans-2-hydroxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-1,3-oxathiolane, andmixtures thereof;

Cis-2-benzoyloxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-1,3-oxathiolane,trans-2-benzoyloxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-1,3-oxathiolane,and mixtures thereof; and

Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-3-oxo-1,3-oxathiolane;

Cis-2-hydroxymethyl-5-(N,N′-dimethylamino-methylenecytosin-1′-yl)-1,3-oxathiolane;

Cis-2-succinyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane;

Cis-2-benzoyloxymethyl-5-(6′-chloropurin 9′-yl)-1,3-oxathiolane;trans-2-benzoyloxymethyl-5-(6′-chloropurin-N-9′-yl)-1,3-oxathiolane, andmixtures thereof;

Cis-2-hydroxymethyl-5-(6′-hydroxypurin-9′-yl)-1,3-oxathiolane;trans-2-hydroxymethyl-5-(6′-hydroxypurin-9′-yl)-1,3-oxathiolane; andmixtures thereof;

Cis-2-benzoyloxymethyl-5-(uracil-N-1′-yl)-1,3-oxathiolane,trans-2-benzoyloxymethyl-5-(uracil-1′-yl)-1,3-oxathiolane, and mixturesthereof;

Cis-2-hydroxymethyl-5-(uracil-1′-yl)-1,3-oxathiolane;

Cis-2-benzoyloxymethyl-5-(thymin-1′-yl)-1,3-oxathiolane,trans-2-benzoyloxymethyl-5-(thymin-1′-yl)-1,3-oxathiolane, and mixturesthereof;

Cis-2-hydroxymethyl-5-(thymin-1′-yl)-1,3-oxathiolane;

Cis-2-hydroxymethyl-5-(adenin-9′-yl)-1,3-oxathiolane,trans-2-hydroxymethyl-5-(adenin-9′-yl)-1,3-oxathiolane, and mixturesthereof;

Cis-2-hydroxethyl-5-(inosin-9′-yl)-1,3-oxathiolane,trans-2-hydroxymethyl-5-(inosin-9′-yl)-1,3-oxathiolane, and mixturesthereof;

Cis-2-benzoyloxymethyl-5-(N₄′-acetyl-5′-fluorocytosin-1-yl)-1,3-oxathiolane,trans-2-benzoyloxymethyl-5-(N₄′-acetyl-5′-fluorocytosin-1′-yl)-1,3-oxathiolane,and mixtures thereof;

Cis-2-hydroxymethyl-5-(5′-fluorocytosin-1′-yl)-1,3-oxathiolane,trans-2-hydroxymethyl-5-(5′-fluorocytosin-1′-yl)-1,3-oxathiolane, andmixtures thereof;

Cis-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane,trans-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, and mixturesthereof;

Cis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane,trans-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane, and mixturesthereof;

Cis-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane,trans-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane, and mixturesthereof;

Cis-2-hydroxymethyl-4-(cytosin-1-yl)-1,3-dioxolane,trans-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane, and mixturesthereof;

Cis-2-benzoyloxymethyl-4-(adenin-9′-yl)-1,3-dioxolane,trans-2-benzoyloxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, and mixturesthereof;

Cis-2-hydroxymethyl-4-(adenin-9′-yl)-1,3-dioxolane,trans-2-hydroxymethyl-4-(adenin-9′-yl)-1,3-dioxolane, and mixturesthereof;

Cis-2-benzoyloxylmethyl-4-(2′-amino-6′-chloro-purin-9′-yl)-1,3-dioxolane,trans-2-benzoyloxylmethyl-4-(2′-amino-6′-chloro-purin-9′-yl)-1,3-dioxolane,and mixtures thereof;

Cis-2-hydroxymethyl-4-(2′-amino-6′-chloro-purin-9′-yl)-1,3-dioxolane,trans-2-hydroxymethyl-4-(2′-amino-6′-chloro-purin-9′-yl)-1,3-dioxolane,and mixtures thereof;

Cis-2-hydroxymethyl-4-(2′-amino-purin-9′-yl)-1,3-dioxolane,trans-2-hydroxymethyl-4-(2′-amino-purin-9′-yl)-1,3-dioxolane, andmixtures thereof;

Cis-2-hydroxymethyl-4-(2′,6′-diamino-purin-9′-yl)-1,3-dioxolane,trans-2-hydroxymethyl-4-(2′,6′-diamino-purin-9′-yl)-1,3-dioxolane, andmixtures thereof;

Cis-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane,trans-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane, and mixturesthereof;

Cis-2-hydroxymethyl-5-(N,N-dimethylamino methylenecytosin-1′-yl)-1,3-dioxolane, trans-2-hydroxymethyl-4-(N,N-dimethylaminomethylene cytosin-1′-yl)-1,3-dioxolane, and mixtures thereof;

in the form of a racemic mixture or a single enantiomer.

The compounds of the invention either themselves possess antiviralactivity and/or are metabolizable to such compounds. In particular thesecompounds are effective in inhibiting the replication of retroviruses,including human retroviruses such as human immunodeficiency viruses(HIV's), the causative agents of AIDS.

There is thus provided as a further aspect of the invention a compoundformula (I) or a pharmaceutically acceptable derivative thereof for useas an active therapeutic agent in particular as an antiviral agent, forexample in the treatment of retroviral infections.

In a further or alternative aspect there is provided a method for thetreatment of a viral infection, in particular an infection caused by aretrovirus such as HIV, in a mammal, including man, comprisingadministration of an effective amount of an antiviral compound offormula (I) or a pharmaceutically acceptable derivative thereof.

There is also provided in a further or alternative aspect of thisinvention, use of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof for the manufacture of a medicament forthe treatment of a viral infection.

The compounds of the invention are also useful in the treatment ofAIDS-related conditions such as AIDS-related complex (ARC), persistentgeneralized lymphadenopathy (PGL), AIDS-related neurological conditions(such as dementia), anti-HIV antibody-positive and HIV-positiveconditions, Kaposi's sarcoma, thrombocytopenia purpurea andopportunistic infections.

The compounds of the invention are also useful in the prevention orprogression to clinical illness of individuals who are anti-HIV antibodyor HIV-antigen positive and in prophylaxis following exposure to HIV.

The compounds of formula (I) or the pharmaceutically acceptablederivatives thereof, may also be used for the prevention of viralcontamination of biological fluids such as blood or semen in vitro.

Certain of the compounds of formula (I) are also useful as intermediatesin the preparation of other compounds of the invention.

It will be appreciated by those skilled in the art that referencesherein to treatment extends to prophylaxis as well as the treatment ofestablished infections or symptoms.

It will be further appreciated that the amount of a compound of theinvention required for use in treatment will vary not only with theparticular compound selected but also with the route of administration,the nature of the condition being treated and the age and condition ofthe patient and will be ultimately at the discretion of the attendantphysician or veterinarian. In general, however, a suitable dose will bein the range from about 1 to about 750 mg/kg of body weight per day,such as 3 to about 120 mg per kilogram body weight of the recipient perday, preferably in the range of 6 to 90 mg/kg/day, most preferably inthe range of 15 to 60 mg/kg/day.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example as two,three, four or more sub-doses per day.

The compound is conveniently administered in unit dosage form; forexample containing 10 to 1500 mg, conveniently 20 to 1000 mg, mostconveniently 50 to 700 mg of active ingredient per unit dosage form.

Ideally the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 1 to 75 μM,preferably about 2 to 50 μM, most preferably about 3 to about 30 μM.This may be achieved, for example, by the intravenous injection of a 0.1to 5% solution of the active ingredient, optionally in saline, oradministered as a bolus containing about 0.1 to about 110 mg/kg of theactive ingredient. Desirable blood levels may be maintained by acontinuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or byintermittent infusions containing about 0.4 to about 15 mg/kg of theactive ingredient.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical it is preferable topresent the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulationcomprising a compound of formula (I) or a pharmaceutically acceptablederivative thereof together with one or more pharmaceutically acceptablecarriers thereof and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.The formulations may, where appropriate, be conveniently presented indiscrete dosage units and may be prepared by any of the methods wellknown in the art of pharmacy. All methods include the step of bringinginto association the active compound with liquid carriers or finelydivided solid carriers or both and then, if necessary, shaping theproduct into the desired formulation.

Pharmaceutical formulations suitable for oral administration mayconveniently be presented as discrete units such as capsules, cachets ortablets each containing a predetermined amount of the active ingredient;as a powder or granules; as a solution; as a suspension; or as anemulsion. The active ingredient may also be presented as a bolus,electuary or paste. Tablets and capsules for oral administration maycontain conventional excipients such as binding agents, fillers,lubricants, disintegrants, or wetting agents. The tablets may be coatedaccording to methods well known in the art. Oral liquid preparations maybe in the form of, for example, aqueous or oily suspensions, solutions,emulsions, syrups or elixirs, or may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, emulsifying agents, non-aqueous vehicles (which mayinclude edible oils) or preservatives.

The compounds according to the invention may also be formulated forparenteral administration (e.g., by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g., sterile, pyrogen-free water, before use.

For topical administration to the epidermis, the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active ingredient in a flavored based, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerin or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Pharmaceutically formulations suitable for rectal administration whereinthe carrier is a solid, are most preferably represented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound with thesoftened or melted carrier(s) followed by chilling and shaping in molds.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient, such carriers as are known in the artto be appropriate.

For intra-nasal administration the compounds of the invention may beused as a liquid spray or dispersible powder or in the form of drops.

Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, solubilizing agents orsuspending agents. Liquid sprays are conveniently delivered frompressurized packs.

For administration by inhalation, the compounds according to theinvention are conveniently delivered from an insufflator, nebulizer or apressurized pack or other convenient means of delivering an aerosolspray. Pressurized packs may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount.

Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form in, for example, capsules or cartridgesor, e.g., gelatin or blister packs from which the powder may beadministered with the aid of an inhalator or insufflator.

When desired, the above described formulations adapted to give sustainedrelease of the active ingredient, may be employed.

The pharmaceutical compositions according to the invention may alsocontain other active ingredients such as antimicrobial agents, orpreservatives.

The compounds of the invention may also be used in combination withother therapeutic agents, for example, other antiinfective agents. Inparticular the compounds of the invention may be employed together withknown antiviral agents.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) or a physiologically acceptablederivative thereof together with another therapeutically active agent,in particular, an antiviral agent.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier thereof comprise a further aspect ofthe invention.

Suitable therapeutic agents for use in such combinations include acyclicnucleosides such as acyclovir, ganciclovir, interferons such as alpha-,beta-and gamma-interferon; glucuronation inhibitors such as probenecid;nucleoside transport inhibitors such as dipyridamole; nucleosideanalogues such as 3′-azido-2′,3′-dideoxythymidine,2′,3′-dideoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine,2′,3′-dideoxythymidine, 2′,3′-dideoxy-2′,3′-didehydrothymidine, and2′,3′-dideoxy-2′,3′-didehydrocytidine and ribavirin; immunomodulatorssuch as interleukin II (IL2) and granulocyte macrophage colonystimulating factor (GM-CSF), erythropoietin, ampligen, thymomodulin,thymopentin, foscarnet, glycosylation inhibitors such as2-deoxy-D-glucose, castanospermine, 1-deoxynojirimycin; and inhibitorsof HIV binding to CD4 receptors such as soluble CD4, CD4 fragments andCD4-hybrid molecules.

The individual components of such combinations may be administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations.

When the compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same virus, the dose of each compound may beeither the same or differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

In the processes for preparing the compounds of this invention, thefollowing definitions are used:

R₁ is a hydrogen, an acyl group having from 1 to 16 carbon atoms, or ahydroxyl protecting group;

R₂ is a purine or pyrimidine base or an analogue or derivative thereof;

R_(x) is substituted or unsubstituted C₁₋₆ alkyl;

R_(y) is substituted or unsubstituted C₁₋₆ alkyl or substituted orunsubstituted aryl;

R_(z) is halo, such as bromo, chloro, iodo or fluoro; and

R is a substituted or unsubstituted, saturated or unsaturated alkylgroup, e.g., a C₁₋₆ alkyl or alkenyl group (such as methyl, ethyl,propyl, butyl, ethenyl, propenyl, allyl, butenyl, etc.); a substitutedor unsubstituted aliphatic or aromatic acyl group, e.g., a C₁₋₆aliphatic acyl group such as acetyl or an aromatic acyl group such asbenzoyl; a substituted or unsubstituted, saturated or unsaturated alkoxyor aryloxy carbonyl group, such as methyl carbonate and phenylcarbonate; substituted or unsubstituted sulphonyl imidazolide;substituted or unsubstituted aliphatic or aromatic amino carbonyl group,such as phenyl carbamate; substituted or unsubstituted alkyl imidategroup such as trichloroacetamidate; substituted or unsubstituted,saturated or unsaturated phosphonate, such as diethylphosphonate;substituted or unsubstituted aliphatic or aromatic sulphonyl group, suchas tosylate; or hydrogen.

Oxathiolane compounds of formula (Ia), i.e., compounds of formula (I)wherein Z is S, S═O or SO₂, and their pharmaceutically acceptablederivatives may be prepared according to the processes discussed hereinor by any method known in the art for the preparation of compounds ofanalogous structure.

One process according to the invention is illustrated in SCHEME 1.Although this process is illustrated using specific reagents andcompounds, it will be obvious to one of skill in the art that suitablealternative reactants may be used to prepare analogous products asdepicted, for example, in SCHEME 1A.

The various steps involved in the synthesis as illustrated in SCHEME 1may be briefly described as follows:

Step 1: Commercial bromoacetaldehyde diethyl acetal (or an analogoushalo alkyl acetal of the formula R_(z)CH₂(OR_(x))₂), is treated inboiling DMF with an excess of potassium thiobenzoate to give thebenzoylthio acetal of formula (V).

Step 2: The benzoyl group of formula (V) is hydrolyzed with sodiumhydroxide in an aqueous organic solvent to give the known mercaptoacetalshown in formula (VI) (G. Hesse and I. Jorder, “Mercaptoacetaldehyde anddioxy-1,4-dithiane”, Chem. Ber., 85, pp. 924-32 (1952)).

Step 3: Glycerol 1-monobenzoate prepared according to the literature (E.G. Hallonquist and H. Hibbert, “Studies on reactions relating tocarbohydrates and polysaccharides. Part XLIV: Synthesis of isomericbicyclic acetal ethers”, Can. J. Research, 8, pp. 129-36 (1933)), isoxidized with sodium meta-periodate to give the knownbenzoyloxyacetaldehyde of formula (VII) (C. D. Hurd and E. M.Filiachione, “A new approach to the synthesis of aldehyde sugars”, J.Am. Chem. Soc., 61, pp. 1156-59 (1939)).

Step 4: The aldehyde of formula (VII) or any aldehyde of the formulaR_(y)COOCH₂CHO is then condensed with the mercaptoacetal of formula (VI)or any mercaptoacetal of the formula HSCH₂CH(OR_(X))₂ in a compatibleorganic solvent, such as toluene, containing a catalytic amount of astrong acid to give the novel intermediate shown in formula (VIII).

Step 5: The 1,3-oxathiolane of formula (VIII) is then reacted with apurine or pyrimidine base (e.g., cytosine) previously silylated with,for example, hexamethyldisilazane in a compatible solvent using a Lewisacid or trimethylsilyl triflate to give intermediate of formula (IX).

Step 6: The amine function of the compound shown in formula (IX) isacetylated with acetic anhydride to yield the intermediate of formula(X) as cis- and trans-isomers which are separated, preferably byfractional crystallization, to give pure cis- (X) and pure trans- (X).

Step 7: The cis- or trans- isomers of formula (X) are treated withmethanolic ammonia to obtain the desired product shown in formula (XI)as cis- and trans-isomers.

Step 8: The preceding isomers of formula (XI) are treated with anoxidizing agent which may be a suitable peracid in a compatible solventto give the 3-oxide (sulfoxide) of formula (XII).

This synthesis is applicable to any nucleoside base analogue, as wouldbe obvious to those skilled in the art of nucleoside chemistry. Othercompounds defined by formula (Ia) may be obtained similarly fromintermediate VII by using the appropriate heterocyclic compound in placeof cytosine in Step 5. In Step 4, other esters of hydroxyacetaldehydesuch as aliphatic acyl or substituted aroyl groups can be used followingthe same sequence of steps leading to the compounds of formula (XI) andformula (XII), respectively.

A second process according to this invention for producing oxathiolanecompounds is illustrated in SCHEME 2. Although this process isillustrated using specific reagents and compounds, it will be obvious toone of skill in the art that suitable analogous reactants may be used toprepare analogous products, as depicted, for example, in SCHEME 2A.

The various steps involved in the synthesis as illustrated in SCHEME 2may be briefly described as follows:

Step 1: A mercaptoacetaldehyde monomer produced from the dimer in asolvent such as pyridine is reacted directly with abenzoyloxyacetaldehyde of formula (VII) or any aldehyde of the formulaR_(y)COOCH₂CHO to yield an oxathiolane lactol of formula (XIII).

Step 2: The hydroxyl group of the compound of formula (XIII) isconverted to a leaving group with a suitable reagent such as acetylchloride in a compatible organic solvent to yield an importantoxathiolane intermediate of formula (XIV).

Step 3: The oxathiolane intermediate of formula (XIV) is reacted with apreviously silylated purine or pyrimidine base to give, for example, acytosin-1′-yl oxathiolane of formula (IX).

Step 4: The amine function of the compound shown in formula (IX) isacylated with acetic anhydride in a solvent such as pyridine to yield acompound of formula (X) which provides for easier separation of isomers.

Step 5: The benzoate and acetyl functions of the compound of formula (X)are hydrolyzed under basic conditions to yield an oxathiolane of formula(XI).

A third process for producing oxathiolane compounds is illustrated inSCHEME 3. Although this process is illustrated using specific reagentsand compounds, it will be obvious to one of skill in the art thatsuitable analogous reactants may be used to prepare analogous products,as depicted, for example, in SCHEME 3A.

The various steps involved in the synthesis as illustrated in SCHEME 3may be briefly described as follows:

Step 1: Mercaptoacetaldehyde monomer produced from the dimer in asolvent such as pyridine is reacted directly with ethyl glyoxylate orany organic glyoxylate of the formula R_(y)OOCCHO to yield anoxathiolane lactol of formula (XV).

Step 2: The hydroxyl group of the compound of formula (XV) is convertedto a leaving group with a suitable reagent such as acetyl chloride in acompatible organic solvent to yield an important oxathiolaneintermediate of formula (XVI).

Step 3: The oxathiolane intermediate of formula (XVI) is reacted with apreviously silylated purine or pyrimidine base, e.g., uracil, in thepresence of a Lewis acid or preferably trimethylsilyl iodide to give,e.g., a uracil-1′-yl oxathiolane of formula (XVII) predominantly as thecis-isomer.

Step 4: The ester group of the oxathiolane of formula (XVII) isselectively reduced with a suitable reducing agent such as sodiumborohydride in a compatible organic solvent such as methanol to yield anoxathiolane nucleoside of formula (XVIII).

Step 5: The hydroxyl group of the compound of formula (XVIII) isprotected with a suitable silyl protecting group such ast-butyl-dimethyl silyl in an appropriate solvent such as dimethylformamide (DMF) to yield an oxathiolane of formula (XIX).

Step 6: The uracil base of formula (XIX) can be interconverted toanother base, such as cytosine, by reaction with a suitable reagent suchas p-chlorophenoxy phosphorous oxychloride followed by amination with,e.g., ammonia in methanol to yield an oxathiolane of formula (XX).

Step 7: The silyl group of the compound of formula (XX) is removed underneutral conditions using a suitable reagent such as tetra n-butylammonium fluoride in a suitable solvent such as tetrahydrofuran to yieldthe oxathiolane of formula (XI).

A fourth process according to this invention for producing oxathiolanecompounds is illustrated in SCHEME 4. Although this process isillustrated using specific reagents and compounds, it will be obvious toone of skill in the art that suitable analogous reactants may be used toprepare analogous products, as depicted, for example, in SCHEME 4A.

The various steps involved in the synthesis as illustrated in SCHEME 4may be briefly described as follows:

Step 1: The hydroxyl group of the intermediate of formula XV, orcorresponding R_(y)-substituted intermediate (see SCHEME 3, step 1), isconverted to a leaving group with a suitable reagent such as methylchloroformate in a compatible organic solvent to yield an importantintermediate of formula (XXI).

Step 2: The ester group of the intermediate of formula (XXI) isselectively reduced with a suitable reducing agent such as sodiumborohydride in a compatible organic solvent such as methanol and theresultant hydroxyl group is directly protected with a suitable groupsuch as t-butyl diphenyl silyl to yield an oxathiolane of formula(XXII).

Step 3: The oxathiolane of formula (XXII) is reacted with a previouslysilylated purine or pyrimidine base, such as cytosine to give, e.g., acytosin-1′-yl oxathiolane of formula (XXIII).

Step 4: The amine function of the compound shown in formula (XXIII) isacylated, e.g., with acetic anhydride in a solvent such as pyridine toyield a compound of formula (XXIV) which provides for easier separationof isomers.

Step 5: The silyl and acetyl functions of the compound of formula (XXIV)are hydrolyzed under basic conditions to yield an oxathiolane of formula(XI).

In a fifth process the oxathiolane compounds of formula (Ia), in which Zis S, S═O or SO₂, may be prepared by the reaction of a compound offormula (LIX)

with a compound of formula (LX)

wherein P is a protecting group, followed by removal of the protectinggroup. The compounds of formula (LIX) may be prepared for reaction by asuitable epoxide (LXI)

with an appropriate sulphur-containing compound, e.g., sodiumthioacetate. Compounds of formula (LXI) are either known in the art ormay be obtained by analagous processes.

In a sixth process of this invention, the oxathiolane compounds offormula (Ia) may be made by converting an intermediate of formula (LXII)

to a compound of formula (Ia) by conversion of the anomeric NH₂ to thedesired purine or pyrimidine base by methods well known in the art ofnucleoside chemistry.

The dioxolane compounds of formula (Ib) and their pharmaceuticallyacceptable derivatives may be prepared by the processes according tothis invention or by any method known in the art for preparation ofcompounds of analogous structure.

One such process for preparing dioxolane compounds of formula (Ib) isoutlined in SCHEME 5. Although this process is illustrated usingspecific reagents and compounds, it will be obvious to one of skill inthe art that suitable alternative reactants may be used to prepareanalogous products, as depicted, for example, in SCHEME 5A.

The various steps involved in the synthesis illustrated in SCHEME 5 maybe briefly described as follows:

Step 1: Chloroacetaldehyde diethyl acetal (or an analogous halo alkylacetal) is treated with glycerol in an inert solvent according to theprocedure reported by E. G. Hallonquist and H. Hibbert, “Studies InReactions Relating To Carbohydrates And Polysaccharides—Part XLIV:Synthesis Of Isomeric Bicyclic Acetal Ethers”, Can. J. Res., 8, pp.129-136 (1933) to produce an intermediate of formula (XXV).

Step 2: The primary alcohol function of the dioxolane intermediate offormula (XXV) is treated with an oxidizing reagent such as chromic acid(which may be complexed with pyridine) in a compatible organic solventto give the corresponding dioxolane carboxylic acid of formula (XXVI).

Step 3: The acid of formula (XXVI) is converted to a mixed anhydrideusing an alkyl chloroformate and subjected to a Baeyer-Villigeroxidation with an organic peracid such as m-chloroperbenzoic acid toyield the corresponding aroyloxydioxolane of formula (XXVII).

Step 4: Intermediate of formula (XXVII) is then reacted with previouslysilylated purine or pyrimidine base such as thymine, with, e.g.,hexamethyldisilazane in a compatible solvent and the reaction catalyzedby a Lewis acid or preferably by trimethylsilyl triflate to give, e.g.,the thymin-1′-yl dioxolane of formula (XVI).

Step 5: The chlorine atom of formula (XXVIII) is displaced by reactionwith a benzoic acid salt in a compatible solvent such as dimethylformamide to give an intermediate of formula (XXIX).

Step 6: The benzoate ester function is then hydrolyzed under basicconditions to yield the desired end-product of formula (XXX).

A second process for preparing further specific dioxolane compounds ofthe present invention is illustrated in SCHEME 6. Although this processis illustrated using specific reagents and compounds, it will be obviousto one of skill in the art that suitable alternative reactants may beused to prepare analogous products, as depicted, for example, in SCHEME6A.

The various steps involved in the synthesis illustrated in SCHEME 6 maybe briefly described as follows:

Step 1: The chlorine atom of starting dioxolane of formula (XXV) isdisplaced by a benzoic (or acetic) acid salt in a solvent such adimethylformamide to yield the diol monoester of formula (XXXI).

Step 2: The hydroxymethyl group of formula (XXXI) is oxidized with asuitable reagent such as chromic acid (which may be complexed withpyridine) in a compatible organic solvent to give the dioxolanecarboxylic acid of formula (XXXII).

Step 3: The acid of formula (XXXII) is then subjected to Baeyer-Villigeroxidation by the procedure outlined in Step 2 of SCHEME 5 above to givethe corresponding aroyloxy-dioxolane of formula (XXXIII). Step 4: Theintermediate of formula (XXXIII) is reacted with a previously silyatedpurine or pyrimidine base, such as cytosine, under the reactionconditions outlined in Step 3 of SCHEME 5 to give, e.g., thecytosin-1′-yl dioxolane of formula (XXXIV).

Step 5: The amine function of formula (XXXIV) is acylated with aceticanhydride in a solvent such as pyridine to give the compound of formula(XXXV) which provides for easier separation of isomers.

Step 6: The ester and acetyl functions of formula (XXXV) are hydrolyzedunder basic conditions to yield the desired end-product of formula(XXXVI).

Step 7: ((XXXIII) to (XXXVII)) The intermediate of formula (XXXIII) isalternatively reacted with a purine or pyrimidine base, such as adenine,by the procedure outlined above in Step 3 of SCHEME 5 to give thecompound of formula (XXXVII).

Step 8: ((XXXVII) to (XXXVIII)) The ester function of formula (XXXVII)is hydrolyzed under basic conditions to yield the desired end-product offormula (XXXVIII).

Step 9: ((XXXIII) to (XXXIX)) The intermediate of formula (XXXIII) isalternatively reacted with 2-amino-6-chloropurine under the conditionsoutlined in Step 3 of SCHEME 5 to give a compound of formula (XXXIX).

Step 10: ((XXXIX) to (XL)) The intermediate (XXXIX) is hydrolyzed underbasic conditions to yield the desired end-product of formula (XL).

Step 11: ((XL) to (XLI)) The chlorine atom of formula (XL) is removed bycatalytic hydrogenation over Pd/C to give the 2′-amino-purin-9′-yldioxolane of formula (XLI).

Step 12: The above intermediate (XXXIX) is alternatively reacted withexcess ammonia under pressure whereupon the 2′,6′-diamino-purin-9′-yldioxolane of formula (XLII) is produced.

Step 13: The compound of formula (XL) is alternatively subjected toboiling sodium hydroxide to give the desired end-product guanin-9′-yldioxolane of formula (XLIII).

A third process for preparing dioxolane compounds of the presentinvention is illustrated in SCHEME 7. Although this process isillustrated using specific reagents and compounds, it will be obvious toone of skill in the art that suitable alternative reactants may be usedto prepare analogous products, as depicted, for example, in SCHEME 7A.

The various steps involved in the synthesis illustrated in SCHEME 7 maybe briefly described as follows:

Step 1: Benzoyloxyacetaldehyde (or any aldehyde of the formulaR_(y)COOCH₂CHO) is converted to the bis(2-methoxyethyl)acetal of formula(XLIV) in, e.g., boiling toluene in the presence of a Lewis acid.

Step 2: The benzoyl group of formula (XLIV) is hydrolyzed with, e.g.,potassium carbonate in an aqueous organic solvent to give thehydroxyacetal shown in formula (XLV).

Step 3: The aldehyde of formula (VII) or any aldehyde of the formulaR_(y)COOCH₂CHO is condensed with the hydroxyacetal of formula (XLV) orany hydroxyacetal of the formula HSCH₂CH(OR_(X))₂ in a compatibleorganic solvent, such as toluene, containing a catalytic amount of astrong acid to give the novel intermediate of formula (XLVI).

Step 4: The 1,3-dioxolane of formula (XLVI) is then reacted with apreviously silylated purine or pyrimidine base, such as cytosine, with,e.g., hexamethyldisilazane in a compatible solvent using a Lewis acidsuch as titanium tetrachloride to give the intermediate of formula(XXXIV).

Step 5: The amine function of the compound of formula (XXIV) isacetylated with acetic anhydride to yield the intermediate (XXXV) foreasier separation of cis- and trans-isomers.

Step 6: The cis- and/or trans-isomers of formula (XXXV) are treatedwith, e.g., methanolic ammonia to give the desired product shown informula (XXXVI) as cis- and trans-isomers.

A preferred process for preparing dioxolane compounds of the presentinvention is illustrated in SCHEME 8. Although this process isillustrated using specific reagents and compounds, it will be obvious toone of skill in the art that suitable alternative reactants may be usedto prepare analogous products, as depicted, for example, in SCHEME 8A.

The various steps involved in the synthesis illustrated in SCHEME 8 maybe briefly described as follows:

Step 1: The aldehyde of formula (VII) or any aldehyde of the formulaR_(y)COOCH₂CHO is condensed with the known epoxide described in R. L.Wasson and H. O. House, “Preparation of Isophorone Oxide”, OrganicSynthesis Collective, Vol. IV, p. 552 (1963) in an appropriate solventsuch as benzene and a suitable Lewis acid such as tetraethylammoniumbromide to give dioxolane of formula (XLVIII).

Step 2: The ketone of formula (XLVIII) is subjected to aBaeyer-Willinger oxidation with an organic peracid such asm-chloroperbenzoic acid to yield the corresponding acetoxydioxolane(XLIX).

Step 3: The dioxolane of formula (XLIX) is then reacted with apreviously silylated purine or pyrimidine base, such as cytosine, with,e.g., hexamethyldisilazane in a suitable solvent using a Lewis acid orpreferrably trimethylsilyl triflate to give the intermediate of formula(XXXIV).

Step 4: The amine function of the compound of formula (XXIV) isacetylated with, e.g., acetic anhydride to yield the intermediate (XXXV)for easier separation of cis- and trans-isomers.

Step 5: The cis- and/or trans-isomers of formula (XXXV) are treated withmethanolic ammonia to give the desired product shown in formula (XXXVI)as cis- and trans-isomers.

In the above-identified processes for making the oxathiolane anddioxolane compounds of this invention, the following intermediates areof particular importance:

2-thiobenzoylacetaldehyde diethylacetal (V);

cis- and trans-2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolane (VIII);

cis- and trans-2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane (XIII);

cis- and trans-2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane (XIV);

cis- and trans-2-ethoxycarbonyl-5-hydroxy-1,3-oxathiolane (XV);

cis- and trans-2-ethoxycarbonyl-5-acetoxy-1,3-oxathiolane (XVI);

cis- and tran-2-ethoxycarbonyl-5-(uracil-1′-yl)-1,3-oxathiolane (XVII);

cis- andtrans-2-t-butyldimethylsilyloxy-methyl-5-(uracil-1′-yl)-1,3-oxathiolane(XIX);

cis- andtrans-2-t-butyldimethylsilyloxy-methyl-5-(cytosin-1′-yl)-1,3-oxathiolane(XX);

cis- and trans-2-ethoxycarbonyl-5-(methoxycarbonyloxy)-1,3-oxathiolane(XXI);

cis- andtrans-2-t-butyldiphenylsilyloxy-methyl-5-(methoxycarbonyloxy)-1,3-oxathiolane(XXII);

cis- andtrans-2-t-butyldiphenylsilyloxy-methyl-5-(cytosin-1′-yl)-1,3-oxathiolane(XXIII);

cis- andtrans-2-t-butyldiphenylsilyloxy-methyl-5-(N₄-acetylcytosin-1′-yl)-1,3-oxathiolane(XXIV);

cis- and trans-2-chloromethyl-4-(m-chloro-benzoyloxy)-1,3-dioxolane(XXVII);

cis- and trans-2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid(XXXII);

cis- and trans-2-benzoyloxymethyl-4-(m-chlorobenzoyloxy)-1,3-dioxolane(XXXIII);

2-benzoyloxyacetaldehyde bis (2-methoxyethyl) acetal (XLIV);

2-hydroxyacetaldehyde bis(2-methoxyethyl)acetal (XLV);

cis- and trans-2-benzoyloxymethyl-4-(2-methoxyethoxy)-1,3-dioxolane(XLVI);

cis- and trans-2-benzoyloxymethyl-4-acetyl-1,3-dioxolane (XLVIII); and

cis- and trans-2-benzoyloxymethyl-4-acetoxy-1,3-dioxolane (XLIX).

In addition, the following intermediates, although not specificallydepicted in the above identified processes, are important intermediatesfor making the oxathiolane and dioxolane compounds of this invention:

2-thiobenzoylacetaldehyde bis(2-methoxyethyl) acetal;

2-thioacetaldehyde bis(2-methoxyethyl acetal;

cis- and trans-2-benzoyloxymethyl-5-(2-methoxyethoxy)-1,3-oxathiolane.

cis- and trans-2-hydroxymethyl-5-hydroxy-1,3-oxathiolane; and

cis- and trans-2-acetoxymethyl-5-1,3-oxathiolane.

Many of the reactions described hereinabove have been extensivelyreported in the context of purine nucleoside synthesis, for example, in“Nucleoside Analogues—Chemistry, Biology and Medical Applications”, R.T. Walker et al., Eds, Plenum Press, New York (1979) at pages 193-223,the text of which is incorporated by reference herein.

As used in the processes of this invention, a “leaving group” is an atomor group which is displaceable upon reaction with an appropriate base,with or without a Lewis acid. Suitable leaving groups include alkoxycarbonyl groups such as ethoxy carbonyl; halogens such as iodine,bromine, chlorine, or fluorine; amido; azido; isocyanato; substituted orunsubstituted, saturated or unsaturated thiolates, such as thiomethyl orthiophenyl; substituted or unsubstituted, saturated or unsaturatedselenino compounds, such as phenyl selenide or alkyl selenide;substituted or unsubstituted, saturated or unsaturated aliphatic oraromatic ketones such as methyl ketone; or —OR where R is a substitutedor unsubstituted, saturated or unsaturated alkyl group, e.g., C₁₋₆ alkylor alkenyl group; a substituted or unsubstituted aliphatic or aromaticacyl group, e.g., a C₁₋₆ aliphatic acyl group such as acetyl and anaromatic acyl group such as benzoyl; a substituted or unsubstituted,saturated or unsaturated alkoxy or aryloxy carbonyl group, such asmethyl carbonate and phenyl carbonate; substituted or unsubstitutedsulphonyl imidazolide; substituted or unsubstituted aliphatic oraromatic amino carbonyl group, such as phenyl carbamate; substituted orunsubstituted alkyl imidate group such as trichloroacetamidate;substituted or unsubstituted, saturated or unsaturated phosphonates,such as diethylphosphonate: substituted or unsubstituted aliphatic oraromatic sulphonyl group, such as tosylate; or hydrogen.

It will be appreciated that the reactions of the above-describedprocesses may require the use of, or conveniently may be applied to,starting materials having protected functional groups, and deprotectionmight thus be required as an intermediate or final step to yield thedesired compound. Protection and deprotection of functional groups maybe effected using conventional means. Thus, for example, amino groupsmay be protected by a group selected from aralkyl (e.g., benzyl), acylor aryl (e.g., 2,4-dinitrophenyl); subsequent removal of the protectinggroup being effected when desired by hydrolysis or hydrogenolysis asappropriate using standard conditions. Hydroxyl groups may be protectedusing any conventional hydroxyl protecting group, for example, asdescribed in “Protective Groups in Organic Chemistry”, Ed. J. F. W.McOmie (Plenum Press, 1973) or “Protective Groups in Organic Synthesis”by Theodora W. Greene (John Wiley and Sons, 1981). Examples of suitablehydroxyl protecting groups include groups selected from alkyl (e.g.,methyl, t-butyl or methoxymethyl), aralkyl (e.g., benzyl, diphenylmethylor triphenylmethyl), heterocyclic groups such as tetrahydropyranyl,acyl, (e.g., acetyl or benzoyl) and silyl groups such as trialkylsilyl(e.g., t-butyldimethylsilyl). The hydroxyl protecting groups may beremoved by conventional techniques. Thus, for example, alkyl, silyl,acyl and heterocyclic groups may be removed by solvolysis, e.g., byhydrolysis under acidic or basic conditions. Aralkyl groups such astriphenylmethyl may similarly be removed by solvolysis, e.g., byhydrolysis under acidic conditions. Aralkyl groups such as benzyl may becleaved, for example, by treatment with BF₃/etherate and aceticanhydride followed by removal of acetate groups so formed at anappropriate stage in the synthesis. Silyl groups may also convenientlybe removed using a source of fluoride ions such as tetra-n-butylammoniumfluoride.

In the above processes the compounds of formula (I) are generallyobtained as a mixture of the cis and trans isomers.

These isomers may be separated, for example, by acetylation, e.g., withacetic anhydride followed by separation by physical means, e.g.,chromatography on silica gel and deacetylation, e.g., wish methanolicammonia or by fractional crystallization.

Pharmaceutically acceptable salts of the compounds of the invention maybe prepared as described in U.S. Pat. No. 4,383,114, the disclosure ofwhich is incorporated by reference herein. Thus, for example, when it isdesired to prepare an acid addition salt of a compound of formula (I),the product of any of the above procedures may be converted into a saltby treatment of the resulting free base with a suitable acid usingconventional methods. Pharmaceutically acceptable acid addition saltsmay be prepared by reacting the free base with an appropriate acidoptionally in the presence of a suitable solvent such as an ester (e.g.,ethyl acetate) or an alcohol (e.g., methanol, ethanol or isopropanol).Inorganic basic salts may be prepared by reacting the free base with asuitable base such as an alkoxide (e.g., sodium methoxide) optionally inthe presence of a solvent such as an alcohol (e.g., methanol).Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compounds offormula (I) using conventional methods.

A compound of formula (I) may be converted into a pharmaceuticallyacceptable phosphate or other ester by reaction with a phosphorylatingagent, such as POCl₃, or a suitable esterifying agent, such as an acidhalide or anhydride, as appropriate. An ester or salt of a compound offormula (I) may be converted to the parent compound, for example, byhydrolysis.

Where the compound of formula (I) is desired as a single isomer it maybe obtained either by resolution of the final product or bystereospecific synthesis from isomerically pure starting material or anyconvenient intermediate.

Resolution of the final product, or an intermediate or starting materialtherefore may be effected by any suitable method known in the art: seefor example, Stereochemistrv of Carbon Compounds, by E. L. Eliel (McGrawHill, 1962) and Tables of Resolving Agents, by S. H. Wilen.

The invention will be further described by the following examples whichare not intended to limit the invention in any way. All temperatures arein degrees celsius.

EXAMPLES Example 1

2-thiobenzoyl acetaldehyde diethylacetal

C₆H₅COS—CH₂CH(OC₂H₅)₂  (V)

To a solution of potassium t-butoxide (11.5 g. 0.11 mol) in DMF (100 ml)was added thiobenzoic acid (17 g. 0.11 mol) and the solution partiallyevaporated in vacuo, benzene added in two consecutive portions (2×30 ml)and evaporated in vacuo each time. To the residual DMF solution wasadded bromoacetaldehyde diethylacetal (20.3 g. 0.1 mol) and the mixturestirred at 120° for 15 h. After cooling, it was poured onto water (500ml), the product extracted with ether (3×200 ml), the extract washedwith aqueous NaHCO₃ followed by water, then dried and the solventremoved in vacuo. The residue was distilled in vacuo to give 17.2 g. ofpure (V), b.p. 131-133°/0.07 mm. It was characterized by ¹H NMR δ(ppm inCDCl₃):

7.97 (d, 2H; aromatic);

7.47 (m, 3H; aromatic);

4.59 (t, 1H; —CH(OC₂H₅)₂));

3.66 (m, 4H; 2×OCH ₂CH₃);

3.30 (d, 2H; SCH₂—);

1.23 (t, 6H; 2×OCH ₂CH₃);

Example 2

Mercaptoacetaldehyde diethylacetal

HSCH₂CH(OC₂H₅)₂  (VI)

The preceding thiobenzoyl derivative (V) (17.2 g) was dissolved in 100ml THF followed by the addition of 6 g NaOH in 20 ml H₂O. The mixturewas refluxed under N₂ for 15 h, then cooled and diluted with water (200ml) and the product extracted with ether (3×200 ml). The extract wasdried, the solvent removed in vacuo and the residue distilled in vacuoto yield 7.1 g of pure (VI), b.p. 60-62°/18 mm. It was characterized by¹H NMR δ(ppm in CDCl₃):

4.51 (t, 1H; CH(OC₂H₅)₂);

3.51 (m, 4H; 2×OCH ₂CH₃);

2.65 (dd, 2H; HS—CH ₂);

1.54 (t, 1H; HS—);

1.23 (t, 6H; 2×OCH ₂CH₃).

Example 3

Benzoyloxyacetaldehyde

C₆H₅COOCH₂CHO  (VII)

This known intermediate was prepared by a previously unreported methodfrom the known 1-benzoyl glycerol. Thus, 50 g of the latter in a mixtureof 500 ml of CH₂Cl₂ and 25 ml of H₂O was treated portion-wise with 80 gof NaIO₄ under vigorous stirring at room temperature. After addition,stirring was continued for 2 h after which time 100 g of MgSO₄ was addedand stirring continued for 30 min. The mixture was filtered, thefiltrate evaporated in vacuo and the residue distilled in vacuo to yield26 g of pure (VII) b.p. 92-94°/0.25 mm. ¹H NMR (200 MH_(z); TMS asinternal reference) δ(ppm in CDCl₃):

9.71 (s, 1H; —CHO);

8.11 (d, 2H: aromatic);

7.60 (m, 1H; aromatic);

7.46 (m, 2H; aromatic);

4.88 (s, 2H; —CH ₂CHO).

Example 4

2-Benzoyloxymethyl-5-ethoxy-1,3-oxathiolane

The preceding mercaptoacetaldehyde acetal (VI) (7 g) was mixed in 100 mlof toluene with 7 g of the above benzoyloxyacetaldehyde (VII), a fewcrystals of para-toluene sulfonic acid added and the mixture placed inan oil-bath at 120° under N₂. The formed ethanol was allowed to distillover, the mixture kept at 120° for an additional 30 minutes, then cooledand washed with aqueous NaHCO₃, dried and evaporated in vacuo. Theresidue was distilled in vacuo to yield 9.8 g of pure (VIII) as amixture of cis- and trans-isomers, b.p. 140-143°/0.1 mm; R_(f) 0.51(hexane-EtOAc); ¹H NMR δ(ppm in CDCl₃):

8.05 (m, 2H; aromatic);

7.57 (m, 1H; aromatic);

7.43 (m, 2H; aromatic);

5.55 (m, 2H; C₅—H, C₂—H);

4.55 (m, 2H; C₂—C₆H₅CO₂CH₂);

3.80 (m, 1H; C₅—OCHCH₃);

3.76 (m, 1H; C₅—OCHCH₃);

3.17 (m, 2H; C₄—H ₂);

1.21 (t, 3H; C₅—OCH₂CH ₃).

Example 5

Cis- and trans-2-benzoyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane

A mixture of 2.7 g of cytosine, 30 ml of hexamethyldisilazane (HMDS) and0.3 ml of trimethylsilyl chloride (TMSCl) was heated under reflux underdry N₂ until a clear solution resulted (3 hours) and the excess reagentsevaporated in vacuo. The remaining volatiles were removed under highvacuum (15 min.), the solid residue taken up in 250 ml of 1,2-dichloroethane and 5 g of the above intermediate (VIII) in 50 ml ofdichloroethane added under dry argon followed by 4.7 ml oftrimethylsilyl triflate (TMST_(f)). After 3 days of heating under refluxunder argon, it was cooled and poured onto 300 ml of saturated aqueousNaHCO₃. The organic layer was collected, the aqueous phase extractedwith CH₂Cl₂ (2×100 ml) and the combined extracts washed with water,dried and evaporated in vacuo. The residue was purified bychromatography on silica gel using CH₂Cl₂:CH₃OH 9:1 as the eluant togive 2.5 g of a pure mixture of cis- and trans-(IX) in a 1:1 ratio asascertained by ¹H NMR. These were separated as the N-acetyl derivativesas described in the following example.

Example 6

Cis- and trans-isomers of2-benzoyloxymethyl-5-(N₄′-acetyl-cytosin-1′-yl)-1,3-oxathiolane

The preceding mixture (IX) (2.5 g) in 100 ml of dry pyridine containing0.1 g of 4-dimethylaminopyridine (DMAP) was treated with aceticanhydride (7 ml) at room temperature and after 16 hours, the mixture waspoured onto cold water followed by extraction with CH₂Cl₂ (3×150 ml).The extract was washed with water, dried, and evaporated in vacuo.Toluene was added to the residue, then evaporated in vacuo and theresidual oil purified by chromatography on silica gel using EtOAc:CH₃OH99:1 as the eluant to yield 1.35 g of pure trans-(X) as the fast movingproduct and 1.20 g of pure cis-(X) as the slow moving component. Thesewere characterized by ¹H NMR spectroscopy.

trans-(X): m.p. 158-160°; R_(f): 0.48 EtOAc:CH₃OH 95:5 U.V.: (CH₃OH)Lambda max: 297 nm ¹H NMR δ(ppm in CDCl₃):

9.00 (b, 1H; C₄′—NH—Ac);

8.06 (m, 2H; aromatic);

7.74 (d, 1H; C₆′—H);

7.56 (m, 1H; aromatic);

7.47 (d, 1H; C₅′—H);

7.45 (m, 2H; aromatic);

6.53 (dd, 1H; C₅—H);

5.89 (dd, 1H; C₂—H);

4.46 (dd, 2H; C₂—CH ₂OCOC₆H₅);

3.66 (dd, 1H; C₄—H);

3.32 (dd, 1H; C₄—H);

2.25 (s, 3H; NH—COCH ₃).

Cis-(X): m.p. 150-152°; R_(f): 0.40 EtOAc:MeOH 95:5) U.V.: (CH₃OH)Lambda max: 297 nm ¹H NMR δ(ppm in CDCl₃):

9.03 (b, 1H; NH—Ac);

8.21 (d, 1H; C₆′—H);

8.05 (m, 2H; aromatic);

7.60 (m, 1H; aromatic);

7.50 (m, 2H; aromatic);

7.29 (d, 1H; C₅′—H)

6.34 (dd, 1H; C₅—H);

5.52 (dd, 1H; C₂—H);

4.80 (dd, 2H; C₂—CH ₂OCOC₆H₅);

3.66 (dd, 1H; C₄—H);

3.24 (dd, 1H; C₄—H);

2.23 (s, 3H; NH—COCH ₃).

Example 7

Cis- and trans-2-hydroxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane

a) Trans-(XI): 375 mg of the preceding trans- (X) was dissolved in 100ml of methanolic ammonia at 24° and after stirring for 16 hours, thesolvent was removed in vacuo and the residue crystallized with ether. Itwas recrystallized from ethanol-ether to yield 174 mg of pure product,m.p. >220° (dec). It was characterized by ¹H and ¹³C NMR. ¹H NMR δ(ppmin DMSO-d₆):

7.57 (d, 1H; C₆′—);

7.18 (d, 2H; C₄′—NH ₂);

6.30 (dd, 1H; C₅—H);

5.68 (d, 1H; C₅′—H);

5.48 (t, 1H; C₂—H);

5.18 (t, 1H; C₂—CH₂OH);

3.45 (m, 3H; C₂—CH ₂OH+C₄ H);

3.06 (dd, 1H; C₄—H).

U.V.: (CH₃OH) Lambda max: 270 nm ¹³C NMR (DMSO-d₆, Varian XL-300); δ inppm:

C₂′ C₄′ C₅′ C₆′ C₅ C₄ C₂ CH₂OH 154.71 165.70 93.47 140.95 87.77 36.1486.80 64.71

b) Cis-(XI): treating 375 mg of cis-(X) by the same preceding procedureled to 165 mg of pure product after recrystallization fromethanol-ether, m.p. 171-173°. It was characterized by ¹H and ¹³C NMR. ¹HNMR: δ(ppm in DMSO-d₆):

7.80 (d, 1H; C₆′—H);

7.20 (d, 2H; C₄′—NH ₂);

6.18 (t, 1H; C₅—H);

5.70 (d, 1H; C₅′—H);

5.14 (t, 1H; C₂—CH₂OH);

3.71 (m, 2H; C₂—CH ₂OH);

3.40 (dd, 1H; C₄—H);

2.99 (dd, 1H; C₄—H).

U.V.: (CH₃OH) Lambda max: 270 nm ¹³C NMR δ(ppm in DMSO-d₆):

C₂′ C₄′ C₅′ C₆′ C₅ C₄ C₂ CH₂OH 154.63 165.59 93.86 140.91 86.47 36.2285.75 62.79

Example 8

Cis-2-hydroxymethyl-5-(cytosin-1′-yl)-3-oxo-1,3-oxathiolane

The preceding cis-(XI) (100 mg) in 30 ml of ice-cold methanol wastreated with 93 mg of metachloroperbenzoic acid and after stirring for15 min a white solid separated which was collected and washed with 10 mlof methanol to give 45 mg of pure sulfoxide isomer a. The methanolfiltrates were evaporated in vacuo and the solid residue washed with 15ml of ethanolether (1:1) and then with 30 ml of ether to give 50 mg ofpure sulfoxide isomer b. The isomers were characterized by ¹H NMR.

Isomer (XII)a: m.p.>270° (dec); R_(f): 0.30 (CH₂Cl₂-MeOH 3:1); U.V.:(CH₃OH) Lambda max: 270 nm ¹H NMR δ(ppm in DMSO-d₆):

7.68 (d, 1H; C₆′—);

7.36 (s, 2H; C₄′—NH ₂);

6.69 (dd, 1H; C₅—H);

5.76 (d, 1H; C₅′—H);

5.47 (t, 1H; C₂—CH₂OH);

4.63 (dd 1H; C₂—H);

3.88 (m, 1H; C₂—CH—OH);

3.72 (m, 1H; C₂—CH—OH);

3.36 (dd, 1H; C₄—H);

3.05 (dd, 1H; C₄—H).

Isomer (XII)b: m.p.>220° (dec); R_(f): 0.32 CH₂Cl₂:MeOH 3:1 ¹H NMR δ(ppmin DMSO-d₆):

7.76 (d, 1H; C₆′—H);

7.28 (d, 2H; C₄′—NH ₂);

6.66 (dd, 1H; C₅—H);

5.77 (d, 1H; C₅′—H);

5.45 (t, 1H; C₂—CH₂OH);

4.64 (t, 1H; C₂—H);

3.77 (t, 2H; C₂—CH ₂OH);

3.65 (dd, 1H; C₄—H);

3.17 (dd, 1H; C₄—H).

Example 9

Cis-2-hydroxymethyl-5-(N,N-dimethylamino methylenecytosin-1′-yl)-1,3-oxathiolane

300 mg of cis-2-hydroxymethyl-5-(cytosin-1′-yl) 1,3-oxathiolane wassuspended in 10 ml of N-dimethylformamide dimethyl acetal (DMF-dimethylacetal). The mixture was stirred at room temperature overnight (18hours). Volatile material was removed by evaporation under reducedpressure. The residue was crystallized in ethanol-ether. It yielded 345mg (93%) of pure product. m.p. 162-164° C.; R_(f): 0.56 in CH₂Cl₂:MeOH4:1 U.V.: Lambda max: 325 nm ¹H NMR δ(ppm in DMSO-d₆):

8.64 (s, 1H, N═CH—N);

8.04 (d, 1H, C₆ ¹—H, J=7.2 Hz);

6.22 (t, 1H, C₅—H, J=4.9 Hz);

5.97 (d, 1H, C₅′—H, J=7.2 Hz);

5.37 (t, 1H, —OH, J=5.8 Hz, D₂O exchange);

5.22 (t, 1H, C₂—H, J=4.4 Hz);

3.77 (t, 2H, C₂—CH₂OH, J=4.9 Hz);

3.50 (dd, 1H, C₄—H, J=4.9 and 9.9 Hz);

3.17 (s, 3H, —CH₃);

3.12 (dd, 1H, C₄—H, J=4.2 and 11.9 Hz);

3.04 (s, 3H, —CH₃).

Example 10

Bis-Cis-2-succinyloxymethyl-5-(cytosin-1′-yl)-1,3-oxathiolane

284 mg of cis-2-hydroxymethyl-5-(N,N-dimethylamino methylenecytosin-1′-yl)-1,3-oxathiolane was dissolved in 10 ml of dry pyridineand cooled at 0° C. in an ice-bath. 60 μl of succinyl chloride was addedvia a syringe. The mixture was stirred overnight (18 hours) and pouredinto 50 ml of saturated aqueous NaHCO₃ solution. The mixture wasextracted with methylene chloride (3×50 ml). The combined CH₂Cl₂solution was washed with water (2×50 ml) and dried over MgSO₄. Afterfiltration, solvent was removed by evaporation under reduced pressure.The foam residue was dissolved in 10 ml of CH₂Cl₂ containing 5 ml ofmethanol. 2 ml of 80% aqueous acetic acid was added and the mixture wasstirred at room temperature overnight. The mixture was evaporated todryness. The solid residue was purified on silica gel using CH₂Cl₂: MeOH4:1 as eluant. It yielded 145 mg (54%) of pure product.

m.p. Dec>230° C.; R_(f): 0.23 (in CH₂Cl₂:MeOH 4:1) U.V.: (MeOH) Lambdamax: 271 nm ¹H-NMR δ(ppm in DMSO-d₆):

7.69 (d, 2H, 2×C ₆′—H, J=7.6 Hz);

7.28 (d, 4H, 2×NH ₂, J=24.9 Hz, D₂O exchange);

6.24 (t, 2H, 2×C ₅—H, J=5.6 Hz);

5.76 (d, 2H, 2×C ₅ ¹—H; J=7.4 Hz);

5.35 (t, 2H, 2×C ₂—H, J=4.5 Hz);

4.37 (d, 4H, 2×C ₂—CH₂O—);

3.42 (dd, 2H, 2×C ₄—H, J=5.5 and 10.9 Hz);

3.10 (dd, 2H, 2×C ₄—H, J=5.6 and 11.7 Hz);

2.60 (s, 4H, 2×—CH ₂—C—O).

Example 11

Cis- andtrans-2-benzoyloxymethyl-5-(6′-chloropurin-9′-yl)-1,3-oxathiolane

1.7 g of 6-chloropurine was heated at reflux in 50 ml of HMDS(hexamethyldisilazane) containing 50 mg of (NH₄)₂SO₄(ammonium sulfate)until the solution became clear (1 hour). Excess HMDS was removed underreduced pressure. The oily residue was dried under high vacuum for 1hour and then dissolved in 100 ml of dry 1,2-dichloroethane.

2.7 g of 2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolane (VIII) was dried ina 500 ml round bottom flask by evaporation twice with 50 ml of benzeneand dissolved in 200 ml of dry 1,2-dichloroethane.

The solution of silylated 6-chloropurine was then transferred into the1,3-oxathiolane solution through a canula under argon atmosphere. 11 mlof 1M TMS-triflate (trimethylsilyl trifluoromethane sulfonate) was addedto the reaction flask. The mixture was heated at reflux for 5 hours,then cooled to room temperature. The mixture was poured into 300 ml ofsaturated sodium bicarbonate solution (NaHCO₃ solution) while stirring.The organic layer was collected and the aqueous phase was extracted withCH₂Cl₂ (2×100 ml). The combined organic phase was washed with water,dried over MgSO₄, filtered and evaporated under reduced pressure. Theresidue was purified and separated on silica gel using Hexane-ethylacetate 7:3 as eluant. It yielded 1.05 g (28%) of the less polarproduct, which was identified as alpha- or trans-isomer as a foam, and710 mg of lower product as beta- or cis-isomer. Total yield 46.1%;cis:trans ratio 1:1.4.

trans-isomer (α-isomer): R_(f): 0.43 in Hexane:EtOAc 1:1. V.: (MeOH)Lambda max: 264.7 nm ¹H-NMR δ(ppm in CDCl₃):

8.76 (s, 1H, C₈′—H);

8.48 (s, 1H, C₂′—H);

8.06 (m, 2H, aromatic);

7.56 (m, 1H, aromatic);

7.45 (m, 2H, aromatic);

6.90 (dd, 1H, C₅—H, J=5.0 Hz);

5.78 (dd, 1H, C₂—H, J=6.0 Hz);

4.56 (m, 2H, C₂—CH₂OCOC₆H₅);

3.74 (m, 2H, C₄—H);

cis-isomer (beta-isomer): R_(f): 0:35 in Hexane:EtOAc: 1:1 U.V.: (MEOH)Lambda max 264.7 nm ¹H-NMR δ(ppm in CDCl₃):

8.72 (s, 1H, C₈′—H);

8.51 (s, 1H, C₂′—H);

8.00 (m, 2H, aromatic);

7.56 (m, 1H, aromatic);

7.45 (m, 2H, aromatic);

6.61 (t, 1H, C₅—H, J=4.7 Hz);

5.62 (t, 1H, C₂—H, J=4.9 Hz);

4.69 (m, 2H, C₂—CH₂OCOC₆H₅);

3.66 (m, 2H, C₄—H).

Example 12

Cis-2-hvdroxymethyl-5-(6′-hydroxypurin-9′-yl)-1,3-oxathiolane (inosinederivative)

533 mg of cis-2-benzoyloxymethyl-5-(6-chloropurin-9′-yl)-1,3-oxathiolanewas dissolved in 25 ml of methanol. 5 g of sodium hydroxide (NaOH) and 3ml of water were added into the solution. The mixture was heated atreflux for 5 hours and cooled to room temperature. The solution was thendiluted with 100 ml of water, neutralized with pyridinium resin andfiltered. The resin residue was washed with 100 ml of methanol. Thecombined filtrate was evaporated under reduced pressure. The residue waspurified on silica gel using CH₂Cl₂:MeOH 4:1 as eluant. It yielded 183mg (51%) of pure product, which was identified as inosine derivative.

m.p.: 208-210° C.; R_(f): 0.27 in EtOAc:MeOH 4:1 U.V.: (MeOH) Lambdamax: 246 nm ¹H-NMR: δ(ppm in DMSO-d₆):

12.42 (s, 1H, —NH, D₂O exchange);

8.36 (s, 1H, C₈′—H);

8.07 (s, 1H, C₂′—H);

6.37 (t, 1H, C₅—H, J=5.1 Hz);

5.29 (t, 1H, —OH, J=6.0 Hz, D₂O exchange);

5.24 (t, 1H, C₂—H, J=4.9 Hz);

3.63 (m, 4H, 2H from C₄—H and 2H from CH₂—OH).

Example 13

Cis- and trans-2-benzoyloxymethyl-5-(uracil-1′-yl)-1,3-oxathiolane

760 mg of uracil was heated at reflux in 30 ml of HMDS in the presenceof 50 mg (NH₄)₂SO₄ until the solution became clear. The mixture wasevaporated under reduced pressure. The residue was dried under highvacuum for 1 hour and dissolved in 100 ml of dry 1,2-dichloroethane.

1.5 g of 2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolane was dried byevaporation twice with 50 ml of benzene in a 500 ml round bottom flaskand dissolved in 150 ml of dry 1,2-dichloroethane.

The silyated uracil solution was transferred into the oxathiolanesolution through a canula under argon atmosphere and 1.5 ml ofTMS-Triflate in 20 ml of 1,2-dichloroethane was added. The reactionmixture was heated at reflux under argon atmosphere for 48 hours, cooledto room temperature and poured into 300 ml of saturated aqueous NaHCO₃solution. The organic layer was collected. The aqueous phase wasextracted twice with CH₂Cl₂ (2×100 ml). The combined organic layer waswashed with water (2×200 ml), once with NaCl solution (1×150 ml) anddried over MgSo₄. After filtration, solvent was removed by evaporationin vacuum and the residue was purified on silica gel using Hexane:EtOAc1:1 as eluant. It yielded 594 mg (32%) of pure product.

The product was shown as only one spot in the TLC. However the ¹H-NMRspectrum indicated the presence of two isomers c:trans in a ratio of1:1.2 and which were not separated at this stage.

R_(f): 0.35 in Hexane:EtoAc 3:7 U.V.: (MeOH) Lambda max: 261 nm ¹H-NMRδ(ppm in CDCl₃)

8.88 (broad s, 1H, N₃′—H);

8.05 (m, 2H, aromatic);

7.71 (d, 1H, C₆′—H cis, J=8.2 Hz);

7.57 (m, 1H, aromatic);

7.45 (m, 3H, aromatic and N₃′—H);

6.55 (dd, 1H, C₅—H trans, J=2.4 and 5.4 Hz);

6.35 (dd, 1H, C₅—H cis, J=4.1 and 5.6 Hz);

5.79 (t, 1H, C₂—H trans, J=5.4 Hz);

5.73 (d, 1H, C₅′—H trans, J=8.2 Hz);

5.57 (d, 1H, C₅′—H cis, J=8.2 Hz);

5.46 (t, 1H, C₂—H cis, J=3.9 Hz);

4.73 (d, 2H, —CH₂O—COC₆H₅);

4.45 (t, 2H, —CH₂OCOC₆H₅);

3.57 (m, 1H, C₄—H);

3.17 (m, 1H, C₄—H).

Example 14

Cis-2-hydroxymethyl-5-(uracil-1′-yl)-1,3-oxathiolane

300 mg of a mixture cis- andtrans-2-benzoyloxymethyl-5-(uracil-1′-yl)-1,3-oxathiolanes was dissolvedin 75 ml of methanolic ammonia. The mixture was stirred at roomtemperature overnight. The solution was evaporated by dryness. Theresidue was purified and the two isomers were separated on silica gelusing EtOAc:MeOH 98:2 as eluant.

The top product was isolated as a solid product and was identified ascis-isomer.

Cis-isomer: m.p. 162-164° C.; R_(f): 0.57 in EtoAc:MeOH 95:5U.V.: (MeOH)Lambda max: 261.4 nm ¹H-NMR δ(ppm in DMSO-d₆):

11.36 (s,1H, N₃′—H);

7.88 (d, 1H, C₆′—H, J=8.1 Hz);

6.18 (t, 1H, C₅—H, J=4.8 Hz);

5.62 (d, 1H, C₅′—H, J=8.1 Hz);

5.33 (t, 1H, C₂—H, J=5.7 Hz);

5.17 (t, 1H, —OH, D₂O exchange);

3.72 (t, 2H, C₂—CH₂OH, J=4.6 Hz);

3.41 (dd, 1H, C₄—H, J=5.7 and 12 Hz);

3.20 (dd, 1H, C₄—H, J=4.6 and 9.9 Hz).

Example 15

Cis- and trans-2-benzoyloxymethyl-5-(thymin-1′-yl)-1,3-oxathiolane

1.7 g of thymine was heated at reflux in 50 ml of HMDS containing 50 mgof (NH₄)₂SO₄ until the solution became clear. The mixture was evaporatedunder reduced pressure. The residue was dried under high vacuum for 1hour and dissolved in 150 ml of 1,2-dichloroethane.

3 g of 2-benzoyloxymethyl-5-ethoxy-1,3-oxathiolane was dried byevaporation twice with 75 ml of benzene and dissolved in 150 ml of dry1,2-dichloroethane.

The silylated thymine solution was transferred into the oxathiolanethrough a canula under argon atmosphere. 3.3 ml of TMS-Triflate(trimethylsilyl-triflate) in 30 ml of dry 1,2-dichloroethane wasintroduced into the reaction mixture through a canula under argonatmosphere. The solution was heated at reflux under argon atmosphere for36 hours, cooled to room temperature and poured into 300 ml of saturatedaqueous NaHCO₃ solution. The organic layer was collected and the aqueousphase was extracted twice with methylene chloride (2×100 ml). Thecombined organic phase was washed twice with water (2×200 ml), once withNaCl solution (1×150 ml) and dried over MgSO₄. The solution wasfiltered. The filtrate was evaporated in vacuum. The residue waspurified on silica gel using Hexane:EtOAc 1:1 as eluant. It yielded 1.3g (35%) of pure product.

The product was shown as only one spot on TLC but the ¹H-NMR spectrumindicated the presence of the two isomers cis and trans in a ratio of1:1.2.

R_(f): 0.30 in Hexane:EtOAc 2:3 U.V.: (MeOH) Lambda max: 266 nm ¹H-NMRδ(ppm in CDCl₃):

8.60 (broad singlett, N₃′—H);

8.06 (m, 2H, aromatic);

7.59 (m, 1H, aromatic);

7.49 (m, 2H, aromatic);

7.38 (d, 1H, C₆′—H-cis, J=1.3 Hz);

7.28 (d, 1H, C₆′—H-trans, J=1.3 Hz);

6.55 (dd, 1H, C₅—H-trans isomer, J=3.1 and 5.6 Hz);

6.38 (t, 1H, C₅—H-cis isomer, J=5.5 Hz);

5.78 (dd, 1H, C₂—H-trans, J=4.4 and 6.4 Hz);

5.46 (t, 1H, C₂—H-cis-isomer, J=4.3 Hz);

4.69 (d, 2H, C₂—CH₂OCOC₆H₅, J=4.2 Hz);

4.45 (m, 2H, C₂—CH₂OCOC₆H₅);

3.58 (m, 1H, C₄—H);

3.13 (m, 1H, C₄—H);

1.93 (d, 1H, C₅′—CH₃-trans isomer, J=1.2 Hz);

1.78 (d, 1H, C₅′—CH₂-cis isomers, J=1.2 Hz).

Example 16

Cis-2-hydroxymethyl-5-(thymin-1′-yl)-1,3-oxathiolane

500 mg of a mixture cis- andtrans-2-benzoyloxymethyl-5-(thymin-N-1′-yl)-1,3-oxathiolanes (XLIX) wasdissolved in 100 ml of saturated methanolic ammonia. The mixture wasstirred at room temperature overnight (18 hours). The mixture was thenevaporated to dryness under reduced pressure. The residue was separatedon silica gel using EtOAc:MeOH 98:2 as eluant.

The less polar product was identified as cis-isomer mp: 167-168° C.;R_(f): 0.66 in EtOAc:MeOH 95:5 U.V.: (MeOH) Lambda max: 266 nm ¹H-NMRδ(ppm in DMSO-d₆):

11.38 (s, 1H, N₃′—H);

7.73 (d, 1H, C₆′—H, J=1.1 Hz);

6.16 (t, 1H, C₅—H, J=5.5 Hz);

5.31 (t, 1H, C₂—H, J=5.9 Hz);

5.14 (t, 1H, OH, D₂O exchange);

3.70 (t, 2H, C₂—CH₂OH, J=5.1 Hz);

3.36 (dd, 1H, C₄—H, J=5.7 and 1.7 Hz);

3.16 (dd, 1H, C₄—H, J=5.5 and 11.7 Hz);

1.75 (d, 3H, C₅′—CH₃, J=1.7 Hz).

Example 17

Cis- andtrans-2-benzoyloxymethyl-5-(N₄′-acetyl-5′-fluoro-cytosin-1′-yl)-1,3-oxathiolane

5-Fluorocytosine (4.30 g, 33.3 mmol), hexamethyldisilazane (25 ml) andammonium sulfate (120 mg) were boiled under reflux until the cytosinedissolved (3 hours) and then further refluxed for 2 hours. Thehexamethyldisilazane is evaporated in vacuo and toluene (100 ml) wasadded to the residue to co-evaporate the solvents. The resultingsolution, bis(trimethylsilyl)-fluoro-cytosine in dichloromethane (40 ml)was added under argon to a solution of2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane (8.537 g, 30.3 mmol) in drydichloromethane (100 ml) and molecular sieves (4 Å, 2 g) previouslyprepared under argon and cooled at 0° C. for 20 minutes.[(Trifluoromethane-sulfonyl)oxy] trimethyl silane (6 ml, 31 mmol) wasadded to this mixture at 0° C. and the resulting solution was stirred at250° C. for approximately 18 hours. The reaction mixture was thentreated with 300 ml of saturated solution of sodium bicarbonate andstirred at room temperature for 2 hours. The filtrate was shaken twotimes with 300 ml of brine and one time with distilled water. Theorganic layer was dried over magnesium sulfate, filtered and evaporatedto dryness. This afforded a crude 5-fluoro-cytosine derivative (10.1 g).R_(f): 0.57 (EtOAc:MeOH 9:1)

This residue was acetylated in the next step without furtherpurification. The crude material was dissolved in dry dichloromethane(120 ml) in a 500 ml round bottom flask under argon. Triethylamine (12.7ml, 91.1 mmol) and dimethyl aminopyridine (111 mg, 0.9 mmol) were addedto the solution. The flask was then immersed in an ice bath for 1 hourunder argon. Acetic anhydride (4.3 ml, 45 mmol), distilled over sodiumacetate, was syringed into the cooled flask. The mixture was stirredovernight and then carefully decanted into an erlenmeyer flaskcontaining saturated sodium bicarbonate solution. The product was thenwashed with distilled water followed by brine solution. The methylenechloride portions were dried and evaporated under high vacuum todryness, yielding an acetylated α/β mixture as a colorless foam,weighing 9.6 g after drying. Flash chromatography of this material usingethylacetate:methanol (9:1) afforded 3.1 g, 7.8 mmol (46%) puretrans-(LI) and 3.5 g, 8.9 mmol (30%) pure cis-(LI).

trans-isomer: R_(f): 0.65 in ethyl acetate:methanol 9:1 U.V.: (MeOH)Lambda max: 309 nm ¹H-NMR δ(ppm in CDCl₃)

8.77 (b, 1H; C₄′—NH—Ac);

8.06 (m, 2H; aromatic);

7.70 (d, 1H; C_(6′) H, J_(6,F)=6.3 Hz);

7.62 (m, 1H; aromatic);

7.49 (m, 2H; aromatic);

6.51 (dd, 1H; C₅—H);

5.91 (dd, 1H; C₂—H);

4.48 (dd, 2H; C₂—CH ₂OCOC₆H₅);

3.66 (dd, 1H; C₄—H);

3.34 (dd, 1H; C₄—H);

2.56 (s, 3H; NH—CoCH ₃).

cis-isomer: R_(f): 0.58 in ethyl acetate:methanol 9:1 U.V.: (MeOH)Lambda max: 309 nm ¹H-NMR δ(ppm in CDCl₃)

8.72 (b, 1H; C₄′—NH—Ac);

8.06 (m, 2H; aromatic);

7.87 (d, 1H; C_(6′)—H, J_(6,F)=6.2 Hz);

7.60 (m, 1H; aromatic);

10 7.49 (m, 2H; aromatic);

6.32 (dd, 1H; C₅—H);

5.47 (dd, 1H; C₂—H);

4.73 (dd, 2H; C₂—CH ₂OCOC₆H₅);

3.62 (dd, 1H; C₄—H);

3.19 (dd, 1H; C₄—H);

2.55 (s, 3H; NH COCH ₃).

Example 18

Cis- and trans-hydroxymethyl-5-(5′-fluorocytosin-1′-yl)-1,3-oxathiolane

1.0 g (2.54 mmol) oftrans-2-benzoyloxymethyl-5-(N₄′-acetyl-5′-fluoro-cytosin-1′-yl)-1,3-oxathiolanewas stirred in 25 ml of methanolic ammonia at 0° C. for 1 hour and thenovernight at room temperature. The mixture was evaporated under reducedpressure. The residue was triturated twice (2×30ml) with anhydrousether. The solid residue was recrystallized in absolute ethanol to give484 mg (1.95 mmol, 77%) of desired product trans-(LII): m.p. 219-221°C.; R_(f)=0.21 in ethyl acetate: methanol (9:1), which was identified by¹H, ¹³C-NMR and U.V. Lambda max (H₂O) 280.9 nm.

1.2 (3.05 mmol) ofcis-2-benzoyloxymethyl-5-(N₄′-acetyl-5′-fluoro-cytosin-1′-yl)-1,3-oxathiolanewas stirred in 30 ml of methanolic ammonia at 0° C. for 1 hour and thenovernight at room temperature. The mixture was evaporated under reducedpressure. The residue was triturated twice (2×30ml) with anhydrousether. The solid residue was recrystallized in absolute ethanol to give655 mg (2.64 mmol, 87%) of pure product cis-(LII): m.p. 204-206° C.;R_(f)=0.21 in ethylacetate: methanol (9:1). The desired compound wasidentified by ¹H, ¹³C-NMR and U.V.Lambda max (H₂O) 280.9 nm.

trans-isomer: ¹H-NMR δ(ppm in DMSO-d₆):

7.85 (d, 1H; C_(6′)—H, J_(CF)=7.01 Hz);

7.83 (d, 2H; C₄′—NH ₂);

6.30 (dd, 1H; C₅—H);

5.60 (t, 1H; C₂—H);

5.18 (t, 1H; C₂—CH₂—OH);

3.49 (m, 3H; C₂—CH ₂OH+C₄ H);

3.17 (dd, 1H; C₄—H);

¹³C NMR (DMSO-d₆), Varian XL 300); δ in ppm

C₂′ C₄′ C₅′ C₆′ 153.47 158.20 134.65 126.24 (²J_(CF) = 13.2 Hz) (JCF =26.2 Hz) (²JCF = 32.0 H_(z)) C₅ C₄ C₂ CH₂OH  88.20  6.18  87.16  62.71

cis-isomer: ¹H-NMR δ(ppm in DMSO-d₆);

8.22 (d, 1H; C_(6′)—H, J_(CF)=7.26 Hz);

7.84 (d, 2H; C_(4′)—NH ₂);

6.16 (t, 1H; C₅—H);

5.43 (t, 1H; C₂—CH₂—OH);

5.19 (t, 1H; C₂—H);

3.77 (m, 2H; C₂—CH ₂OH);

3.35 (dd, 1H; C₄—H);

3.12 (dd, 1H; C₄—H).

¹³C NMR (DMSO-d₆):

C₆ ^(′) C₂ ^(′) C₄ ^(′) C₅ ^(′) 153.46 158.14 134.63 126.32 (²J_(CF) =14.0 Hz) (J_(CF) = 24.1 Hz) (J_(CF) = 32.5 Hz) C₅ C₄ C₂ CH₂OH 86.8236.80 86.77 62.32

Example 19

2-chloromethyl-1,3-dioxolane-4-carboxylic acid

Starting material (XXV) (40 g; prepared according to E. G. Hallonquistand H. Hibbert, Can. Res. J. 1933, 7, 129) was treated with pyridiniumdichromate (PDC; 345 g) in dimethyl formamide (DMF; 690 ml) at 0°according to the procedure of E. J. Corey and G. Schmidt, TetrahedronLett., 1979, 399 and product (XXVI) obtained as a crude mixture of cis-and trans-isomers (20 g) was identified by its ¹H NMR spectrum [200 MHz,CDCl₃; tetramethyl silane (TMS) as internal reference]. δ(ppm):

3.6-3.8 (m,2H; CH ₂Cl);

4.1-4.5 (m,2H; C₅ H ₂);

4.72-4.797 (qq,1H; C₄—H);

5.29-5.46 (tt,1H; C₂—H).

The produce was used as such in the next step.

Example 20

Cis- and trans-2-chloromethyl-4-m-chlorobenzoyloxy-1,3-dioxolane

The preceding product (XXVI) (5.26 g) was treated in CH₂Cl₂ at −20° with3.6 ml of ethyl chloroformate in the presence of 4.5 of triethylamine.To the solution was added 8.85 g of m-chloroperbenzoic acid at roomtemperature according to the procedure of D. H. R. Barton, I. H. Coatesand P. G. Sammes, J. Chem. Soc., Perkin 1, 1973, 599 to give (XXVII) asa mixture of cis- and trans-isomers. These were separated and purifiedby flash chromatography on silica gel using a mixture of hexanes andethyl acetate as the eluent. The isomers were identified by their ¹H NMRspectra (recorded as in example 19): trans-isomer of (XXVII): δ(ppm):

3.66 (q,2H; CH ₂—Cl);

4.36 (qq,2H; C₅—H ₂);

5.57 (t,1H; C₂—H);

6.7 (q,1H; C₄—H);

7.39-8.0 (m,4H; aromatic H);

cis-isomer of (XXVII): δ(ppm):

3.66 (q,2H; CH ₂Cl);

4.24 (qq,2H; C₅—H ₂);

5.43 (t,1H; C₂—H);

6.63 (q,1H; C₄—H);

7.42-8.04 (m,4H; aromatic H).

Example 21

2-chloromethyl-4-(thymin-1′-yl-1,3-dioxolane

Reaction of the preceding compound with thymine was carried outaccording to the procedure of D. S. Wise and L. B. Townsend, in NucleicAcid Chemistry, Eds. L. B. Townsend and R. S. Tipson, John Wiley & Sons,Inc., New York, 1978, Part 1, pp. 413-419. The product was a mixture ofcis- and trans-isomers of (XXVIII) (37.3 mg from 131 mg of (XXVII))which had the following ¹H NMR characteristics (obtained as in example19): δ(ppm):

1.93 (d,3H; 5′—CH ₃);

3.64 and 3.85 (dd,2H; CH ₂Cl);

4.17-4.46 (m,2H; C₅—H ₂);

5.26 and 5.72 (tt,1H; C₂—H);

6.6 and 6.66 (qq,1H; C₄—H);

7.40 and 7.49 (dd,1H; C_(6′)—H);

U.V.: (CH₃OH) max.264 nm.

Example 22

Cis- and trans-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane

The preceding compound (XXVIII) (35 mg) was reacted with anhydrouspotassium acetate (70 mg) in boiling DMF (3 ml) for 4 h to give afterconventional workup a cis- and trans-mixture of (XXIX) (25 mg). Theseisomers were purified and separated by flash chromatography on silicausing a mixture of hexanes and ethyl acetate as the eluent. Their ¹H NMRspectra were as follows:

trans-isomer of (XXIX): δ(ppm):

1.94 (d,3H; C₅′—CH ₃);

2.12 (s,3H; CH ₃CO₂—);

4.05-4.43 (m,4H; C₂—CH ₂—O₂CCH₃ and C₅—H ₂);

5.65 (t,1H; C₂—H);

6.31 (q,1H; C₄—H);

7.14 (d,1H; C_(6′)—H);

8.18 (m,1H;N_(3′)—H).

cis-isomer of (XXIX): δ(ppm):

1.97 (d,3H; C_(5′)CH ₃);

2.14 (s,3H; CH ₃CO—O);

4.13-4.49 (m,4H;2—CH ₂OCOCH₃ and C₅ H ₂);

5.19 (t,1H; C₂—H);

6.40 (q,1H; C₄ H);

7.43 (d,1H; C_(6′)—H);

8.12 (m,1H;N_(3′)—H).

U.V.: (CH₃OH) max.264 nm.

Example 23

Cis- and trans-2-hydroxymethyl-4-(thymin-1′-yl)1,3-dioxolane

The preceding trans- and cis-isomers of XXIX (10 mg) were respectivelytreated with a catalytic amount of potassium carbonate in methanol (5ml) at room temperature for 5-6 h and the mixture worked up in the usualmanner and the respective products purified by flash chromatography onsilica gel using a mixture of ethyl acetate and methanol as the eluent.The ¹H NMR spectrum of the pure trans-isomer of (XXX) was as follows (inCD₃COCD₃ as solvent); trans-(XXX): δ(ppm):

1.87 (d,3H; C_(5′)—CH ₃);

3.61 (q;2H; C₂—CH ₂OH);

4.30 (qq,2H; C₅—H ₂);

5.56 (t,1H; C₂—H);

6.31 (q,1H; C₄—H);

7.41 (d,1H; C_(6′) H).

U.V.: (CH₃OH) max.265 nm.

cis-isomer of (XXX) (in CD₃COCD₃): δ(ppm):

1.82 (d,3H; C_(5′)—CH ₃);

3.82 (q,2H; C₂CH ₂OH);

4.24 (qq,2H; C₅—H ₂);

5.02 (t,1H; C₂—H);

6.34 (q,1H; C₄—H);

7.81 (d,1H; C_(6′)—H).

U.V.: (CH₃OH) max.264 nm.

Example 24

2-benzoyloxymethyl-4-hydroxymethyl-1,3-dioxolane

Starting material XXV (41.6) was treated with potassium benzoate (65.56g) in boiling dimethyl formamide containing 100 mg of 18-crown-6 for 24h after which time the mixture was worked up in the usual manner and theproduct (51.02 g) characterized by its ¹H NMR spectrum (CDCl₃;TMS):δ(ppm):

3.5-4.8 (m7H; C₅—H ₂; C₂—CH ₂OCOC₆H₅,C₄—CH ₂OH and C₂—H);

5.05 and 5.16 (tt,1H; C₄—H);

7.27-8.10 (m,5H; aromatic H).

Similar results were obtained using potassium acetate instead ofpotassium benzoate.

Example 25

2-benzoyloxymethyl-1,3-dioxolane-4-carboxylic acid

The preceding compound (XXXI) (51.02 g) was treated at 0° withpyridinium dichromate (282.5 g) in dimethyl formamide (565 ml) and themixture worked up in the usual manner to give 35 g of crude (XXXII)which was used as such in the next example.

Example 26

Cis- and trans-2-benzoyloxymethyl-4-(m-chlorobenzoyloxy)-1,3-dioxolane

A 10 g portion of crude (XXXII) was treated with 6.03 ml of ethylchloroformate in the presence of 8.6 ml of triethylamine followed by theaddition of 16.81 g of m-chloroperbenzoic acid exactly as described inexample 20 for the case of the preparation of intermediate (XXVII). Theisomers of product (XXXIII) thus obtained were purified by flashchromatogaphy on silica gel using a mixture of hexanes and ethyl acetateas the eluent. They were characterized by their ¹H NMR spectra (CDCl₃);

trans-isomer of (XXXIII): δ(ppm):

4.29 (qq,2H; C₅—H ₂);

4.49 (d,2H; C₂—CH ₂OCOC₆H₅);

5.66 (t,1H; C₂—H);

6.70 (q,1H; C₄—H);

7.27-8.10 (m,9H; aromatic).

cis-isomer of (XXXIII): δ(ppm):

4.27 (qq,2H; C₅—H ₂);

4.51 (d,2H; C₂—CHOCOC₆H₅);

5.51 (t,1H; C₂—H);

6.59 (d,1H; C₄ H);

7.26-8.09 (m,9H; aromatic).

Example 27

2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane

Following the procedure described by T. Ueda and S. I. Watanabe, Chem.Pharm. Bull. (Japan), 1985, 33, 3689-3695 and by G. Gosselin, M. C.Bergogne, J. DeRudder, E. DeClercq and J. L. Imbach, J. Med., Chem,1987, 30, 982-991, cytosine (139 mg) and either isomer of the precedingcompound (XXXIII) (363 mg) yielded a mixture of cis- and trans-isomers(390 mg) (XXXIV) which were used as such in the following step.

Example 28

Cis- andtrans-2-benzoyloxymethyl-4-(N-acetylcytosin-1′-yl)-1,3-dioxolane

Treatment of cis- and trans-(XXXIV) with excess acetic anhydride inpyridine at room temperature yielded after work up in the conventionalmanner, a mixture of the cis- and trans-isomers of (XXXV) which wereseparated and purified by flash chromatography on silica gel using amixture of hexanes and ethyl acetate as the eluent. They werecharacterized by their ¹H NMR spectra (CDCl₃): trans-isomer of (XXXV):δ(ppm):

2.15 (s,3H; C_(4′)—NH—COCH ₃);

4.16 and 4.46 (m,4H; C₅—H ₂ and C₂—CH ₂OCOC₆—H ₅);

5.96 (t,1H; C₂—H);

6.24 (q,1H; C₄—H);

7.55-8.09 (m,5H; aromatic);

8.15 (d,1H; C_(6′)—H);

cis-isomer of (XXXV): δ(ppm):

2.15 (s,3H; C_(4′)—NH—COCH ₃);

4.26 and 4.56 (m,4H; C₅—H ₂ and C₂—CH ₂OCOC₆—H₅);

5.35 (t,1H; C₄—H);

6.25 (q,1H; C₄—H);

7.18 (d,1H; C₅,—H);

7.58-8.04 (m,5H; aromatic);

8.17 (d,1H; C₆,—H).

Example 29

Cis- and trans-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane

Each of the preceding isomers of (XXXV) (25 mg) was treated withpotassium carbonate (20 mg) in methanol at room temperature for severalhours and the mixtures worked in the usual manner to yield each isomerof (XXIV) which were purified by chromatography on silica gel using amixture of ethyl acetate and methanol an eluent. They were crystallizedfrom methanol and characterized by their respective ¹H NMR spectra(CD₃COCD₃): trans-isomer of (XXXVI): m.p. 179-180° δ(ppm):

3.62 (q,2H; C₂—CH ₂OH);

4.21 (qq,2H; C₅—H ₂);

5.50 (t,1H; C₂—H);

5.93 (d,1H; C_(5′)—H, J=7.5 Hz);

6.18 (q,1H; C₄—H);

7.66 (d,1H; C₆,—H, J=7.5 Hz).

U.V.: (CH₃OH) max.271 nm. cis-isomer of (XXXVI): m.p.173-174° δ(ppm):

3.82 and 4.15 (m,4H; C₅—H ₂ and C₂—CH ₂OH);

5.04 (t,1H; C₂—H);

5.83 (d,1H; C_(5′)—H);

6.23 (q,1H; C₄—H);

8.05 (d,1H; C_(6′) H);

U.V.: (CH₃OH) max.270 nm.

Example 30

Cis- and trans-2-benzoyloxymethyl-4-(adenin-9′-yl)-1,3-dioxolane

Following the same procedure as in example 27, adenine (135 mg) wascoupled with either isomer of intermediate XXXIII (545 mg) indimethylformamide at 120° in the presence of trimethylsilyl triflate(0.45 ml) and the mixture worked up in the usual manner to yield amixture of cis- and trans-isomers of (XXXVII) (540 mg) which werepurified and separated by chromatography on silica gel using a mixtureof hexanes and ethyl and acetate as the eluent. They were characterizedby their respective ¹H NMR spectra (CDCl₃): trans-isomer of (XXXVII):δ(ppm):

4.5 and 4.59 (m,4H; C₅—H ₂ and C₂—CH ₂OCOC₆H₅);

6.00 (t,1H; C₂—H);

6.65 (q,1H; C₄—H);

6.75 (m,2H; C_(6′) H ₂);

7.68-8.21 (m,5H; aromatic);

8.36 (s,1H; C_(2′)—H);

8.37 (s,1H; C_(8′)—H).

cis-isomer of (XXXVII): δ(ppm):

4.62 (d,2H; C₂—CH ₂OCOC₆H₅);

4.65 (qq,2H; C₅—H ₂);

5.52 (t,1H; C₂—H);

6.59 (q,1H; C₄—H);

6.85 (m,2H; C_(6′)—NH ₂);

6.96-7.71 (m,5H; aromatic);

7.66 (d,2H; C_(2′)—H and C_(8′)—H).

Example 31

Cis- and trans-2-hydroxymethyl-4-(adenin-9′-yl)-1,3 dioxolane

Each isomer of the preceding compound (XXXVII) was treated withpotassium carbonate in methanol at room temperature by the sameprocedure described in example 23 and each product purified by columnchromatography on silica gel using a mixture of ethyl acetate andmethanol as the eluent. The isomers were further purified bycrystallization from methanol and characterized by their ¹N NMR spectra(CD₃SOCD₃): trans-isomer of (XXXVIII): δ(ppm):

3.50 (d,2H; C₂—CH ₂OH);

4.70 (m,2HC₅—H ₂);

5.52 (t,1H; C₂—H);

6.44 (q,1H, C₄—H);

8.18 (s,1H; C_(2′)—H);

8.31 (s,1H; C_(8′)—H).

U.V.: (CH₃OH) max.269 nm.

cis-isomer of (XXXVIII): δ(ppm):

4.63 (d,2H; C₂—CH ₂OH);

4.29 (qq,2H; C₅—H ₂);

5.08 (t,1H; C₂—H);

6.43 (q,1H; C₄—H);

8.18 (s,1H; C_(2′)—H);

8.36(s,1H; C_(8′)—H).

U.V.: (CH₃OH) max.269 nm.

Example 32

Cis- andtrans-2-benzoyloxymethyl-4-(2′-amino-6′-chloro-purin-9′-yl)-1,3-dioxolane

A solution of 2-amino-6-chloropurine (600 mg; 3.54 mmol) in 20 ml ofhexamethyldisilazane (HMDS) containing 0.5 ml of trimethylsilyl chloride(TMS-Cl) was heated under reflux for 3 h after which time the mixturewas evaporated to dryness in vacuo. The residue was dissolved in 75 mlof dichloroethane containing 910 mg of compound (XXXIII) and 0.6 ml oftrimethylsilyl triflate (TMS-T_(f)) added. After refluxing under argonfor 4 h, the mixture was collected, 2 g of solid NaHCO₃ added followedby 50 ml of saturated aqueous NaHCO₃. The organic layer was collectedand after work-up in the usual manner, crude (XXVII) was obtained as anoil which was purified and separated into its isomer by chromatographyon silica gel using hexane-ethyl acetate (3:7) as the eluent to give 230mg of pure trans- and 250 mg or pure cis-isomer as colorless foams. Theywere characterized by their ¹H NMR spectra (CDCl₃): trans-isomer of(XXXIX) R_(f): 0.40; hexane-EtOAc 3:7 δ(ppm):

4.45-4.52 (m,4H; C₅—H ₂,C₂—CH ₂OCOC₆H₅);

5.16 (b,2H; C_(2′)—NH₂);

5.83 (t,1H; C₂—H, J=3.8 Hz);

6.39 (dd,1H; C₄—H);

7.41-7.58 (m,3H; aromatic);

7.92 (s,1H; C_(8′)—H);

8.06 (d,2H; aromatic, J=7 Hz).

U.V.: (CH₃OH) max. 312 nm.

cis-isomer of (XXXIX): R_(f): 0.26, hexane-EtOAc 3:7 δ(ppm):

4.25-4.33 (dd,1H; C₅—H, J=5.43 Hz);

4.59-4.64 (m,3H; C₅—H and C₂—CH₂—OCOC₆H₅);

5.17 (b,2H; C_(2′)—NH₂);

5.42 (t,1H; C₂—H, J=3.50 Hz);

6.33-6.53 (dd,1H; C₄—H);

7.38-7.57 (m,3H; aromatic);

7.93-7.98 (d,2H; aromatic);

8.00 (s,1H; C_(8′)—H).

U.V.: (CH₃OH) max.312 nm.

Example 33

Cis- andtrans-2-hydroxymethyl-4-(2′-amino-6′-chloro-purin-9′-yl)-1,3-dioxolane

The preceding trans-isomer of (XXXIX) (180 mg) was dissolved in 30 ml ofmethanol, the solution cooled to 0° and dry ammonia bubbled through for15 min. After stirring at room temperature for 15 h, the solvent wasremoved in vacuo and the residue crystallized from ether. Afterrecrystallization from ethanol-ether, 98 mg of pure trans-(XL), m.p.155-156°, was obtained (R_(f): 0.23, EtOAc). It was characterized by ¹HNMR (DMSO-d₆): trans-(XL): δ(ppm):

3.44-3.49 (m,2H; C₂—CH ₂OH);

4.37-4.45 (m,2H; C₅—H ₂);

5.01 (t,1H; C₅—CH₂OH, J=6.2 Hz);

5.46 (t,1H; C₂—H, J=3.6 Hz);

6.27-6.32 (dd,1H; C₄—H, J=4,1 Hz);

7.00 (b,2H; C_(2′)—NH ₂);

8.26 (s,1H; C_(8′)—H).

U.V.: (CH₃OH) max.247 and 308 nm.

The cis-isomer of (XL) was obtained in similar yield from the cis-isomerof (XXXIX) by the same preceding procedure. After recrystallization fromethanol-ether, the pure product had m.p. 145-147° (R_(f): 0.24, EtOAc).It was characterized by ¹H NMR (DMSO-d₆): cis-(XL): δ(ppm):

3.54-3.59 (m,2H; C₂—CH ₂OH);

4.12-4.19 (dd,1H; C₅—H, J=5.3 Hz and 9.8 Hz);

4.48-4.53 (d,1H; C₅—H, J=9.8 Hz);

5.01 (t,1H; C₂—H, J=2.8 Hz);

5.09 (t,1H; C₂—CH₂—OH, J=6.0 Hz);

6.24 (d,1H; C₄—H, J=5.1 Hz);

6.96 (b,2H; C₂,—NH₂);

8.23 (s,1H; C_(8′)—H).

U.V.: (CH₃OH) max.247 and 308 nm.

Example 34

Cis- and trans-2-hydroxymethyl-4-2′-amino-purin-9′-yl)-1,3-dioxolane

The preceding trans-isomer of (XL) (50 mg) was submitted tohydrogenation conditions under 50 psi of hydrogen over 10% Pd/C (30 mg)in 30 ml of ethanol containing 0.5 ml of triethylamine. After 3 h ofshaking, the mixture was worked up in the usual manner to yield a solidwhich was recrystallized from ethanol-ether to give 36 mg of puretrans-(XLI), m.p. 153-155°, R_(f): 0.25 (EtOAc: MeOH 85:15). It wascharacterized by ¹H NMR (DMSO-d₆): trans-(XLI): δ(ppm):

3.44-3.49 (m,2H; C₂—CH ₂OH);

4.38-4.44 (m,2H; C₅—H ₂);

4.99 (t,1H; C₂—CH₂—OH, J=6.1 Hz);

5.45 (t,1H; C₂—H, J=3.6 Hz);

6.29-6.34 (dd,1H; C₄—H);

6.59 (b,2H; C_(2′)—NH ₂);

8.19 (s,1H; C_(8′)—H);

8.59 (s,1H; C_(6′)—H);

The cis-isomer of (XLI) was obtained in similar yield from thecis-isomer of (XL) by the same preceding procedure. Afterrecrystallization from ethanol-ether, the pure product had m.p.145-148°, R_(f): 0.25 (EtOAc:MeOH 85:15). It was characterized by ¹H NMR(DMSO-d₆): cis-(XLI): δ(ppm):

3.55-3.60 (dd,2H; C₂—CH ₂H, J=2.10 and 6.1 Hz);

4.14-4.22 (dd,1H; C₅—H, J=5.4 and 9.7 Hz);

4.47-4.53 (dd,1H; C₅—H, J=1.38 and 9.7 Hz);

5.02 (t,1H; C₂—H, J=3 Hz);

5.11 (t,1H; C₂—CH₂OH, J=7.2 Hz);

6.58 (b,2H; C₂—NH ₂);

8.19 (s,1H; C_(8′)—H);

8.57 (s,1H; C_(6′)—H).

U.V.: (CH₃OH) max. 255, 308 nm.

Example 35

Cis- andtrans-2-hydroxymethyl-4-(2′,6′-diamino-purin-9′-yl)-1,3-dioxolane

The above compound trans-(XXXIX) (200 mg) was dissolved in 30 ml ofmethanol saturated at 0° with dry ammonia and the solution heated in asteel bomb to 105-110° for 16 h. The solution was evaporated to drynessand the residue purified by chromatography on silica gel usingchloroform-methanol 4:1 as the eluent to give 101 mg of product whichwas recrystallized from methanol-ether to yield pure trans-(XLII), m.p.165-168°, R_(f): 0.30(CHCl₃; CH₃OH 4:1). It was characterized by ¹H NMR(DMSO-d₆): trans-(XLII): δ(ppm):

3.43-3.48 (m,2H; C₂—CH ₂OH);

4.34-4.49 (m,2H; C₅—H ₂);

4.97 (t,1H; C₂—CH₂OH);

5.42 (t,1H; C₂—H);

5.82 (b,2H; C_(2′)— or C_(6′)—NH ₂);

6.18-6.23 (dd,1H; C₄—H);

6.72 (b,2H; C_(2′)— or C_(6′)—NH ₂);

7.84 (s,1H; C_(8′)—H).

U.V.: (CH₃OH) max.255,280 nm.

The cis-isomer of (XLII) was obtained by the same preceding procedurefrom compound cis-(XXXIX). After recrystallization from methanol-ether,pure cis-(XLII), m.p. 180-182°, R_(f): 0.32(CHCl₃—CH₃OH 4:1) wasobtained in a similar yield. It was characterized by ¹H NMR (DMSO-d₆):cis-(XLII): δ(ppm):

3.56-3.58 (d,2H; C₂—CH₂OH, J=4.2 Hz);

4.11-4.19 (dd,1H; C₅—H, J=4.5 and 9.7 Hz);

4.38-4.44 (dd,1H; C₅—H, J=1.6 and 11.2 Hz);

5.00 (t,1H; C₂—H, J=3.1 Hz);

5.91 (b,2H; C_(2′)— or C_(6′)—NH ₂);

6.15-6.19 (dd,1H; C₄—H);

6.84 (b,2H; C_(2′)— or C_(6′)—NHH₂);

7.86 (s,1H; C_(8′)—H).

U.V.: (CH₃OH) max.254,279 nm.

Example 36

Cis- and trans-2-hydroxymethyl-4-(guanin-9′-yl)-1,3-dioxolane

The above cis-(XL) (40 mg) was dissolved in a mixture of 15 ml ofmethanol, 2 ml of water and 2 g of sodium hydroxide and the solutionheated under reflux for 5 h after which time it was diluted with 100 mlof water and excess pyridinium sulfonate resin added. The slurry wasfiltered, the resin washed with water and the combined aqueous filtratesevaporated to dryness in vacuo to leave a residue which was taken up in50% aqueous methanol. The solution was treated with activated charcoal,filtered and the filtrate evaporated to dryness invacuo to give a solidresidue that was recrystallized from ethanol-water to yield purecis-XLIII (27 mg) m.p. >250° decomp., R_(f): 0.23 (CHCl₃:CH₃OH 7:3). Itwas characterized by ¹H NMR (DMSO-d₆): cis-(XLIII): δ(ppm):

3.55 (m,2H; C₂CH ₂OH);

4.10-4.17 (dd,1H; C₅—H, J=5.6 and 9.8 Hz);

4.37-4.42 (dd,1H; C₅—H, J=1.4 and 9.6 Hz);

4.98 (t,1H; C₂—H, J=3.2 Hz);

5.15 (b,1H; C₂—CH₂OH);

6.10-6.13 (dd,1H; C₄—H, J=2.4 and 5.3 Hz);

6.66 (b,2H; C_(2′)—NH ₂);

7.78 (s,1H; C_(8′)—H);

11.02 (b,1H;N_(1′)—H).

U.V.: (CH₃OH) max.252, 270(shoulder).

The isomer trans-(XLIII) was obtained in similar yield from the abovetrans-(XL) by the same preceding procedure. After recrystallization fromethanol-water, pure trans-(t), m.p. >260°(dec.), R_(f): 0.23(CHCl₃:CH₃OH 7:3) was obtained and characterized by ¹H NMR (DMSO-d₆):trans-(XLIII): δ(ppm):

3.42-3.47 (m,2H; C₂—CH₂OH);

4.34 (d,2H; C₅—H ₂, J=4.8 Hz);

4.99 (t,1H; C₂—CH₂OH);

5.40 (t,1H; C₂—H, J=3.5 Hz);

6.15-6.20 (t,1H; C₄—H, J=4.8 Hz);

6.49 (b,2H; C_(2′)—NH ₂);

7.83 (s,1H; C_(8′)—H);

10.64 (b,1H;N_(1′)—H).

U.V.: (CH₃OH) max.252, 270 (shoulder)

Example 37

Tablet Formulations

A. The following formulation is prepared by wet granulation of theingredients with a solution of povidone in water, drying and screening,followed by addition of magnesium stearate and compression.

mg/tablet (a) Active ingredient 250 (b) Lactose B.P. 210 (c) PovidoneB.P. 15 (d) Sodium Starch Glycolate 20 (e) Magnesium Stearate 5 500

B. The following formulation is prepared by direct compression; thelactose is of the direct compression type.

mg/tablet Active ingredient 250 Lactose 145 Avicel 100 MagnesiumStearate 5 500

C. (Controlled Release Formulation) The formulation is prepared by wetgranulation of the ingredients (below) with a solution of povidone inwater, drying and screening followed by the addition of magnesiumstearate and compression.

mg/tablet (a) Active ingredient 500 (b) Hydroxypropylemethylcellulose112 (Methocel K4M Premium) (c) Lactose B.P. 53 (d) Povidone B.P 28 (e)Magnesium Stearate 7 700

Example 38

Capsule Formulation

A capsule formulation is prepared by admixing the ingredients below andfilling into a two-part hard gelatin capsule.

mg/capsule Active ingredient 125 Lactose 72.5 Avicel 50 MagnesiumStearate 2.5 250

Example 39

Injectable Formulation Active ingredient 0.200 g Sodium hydroxidesolution, 0.1M q.s. to a pH of about 11. Sterile water q.s. to 10 ml.

The active ingredient is suspended in some of the water (which may bewarmed) and the pH adjusted to about 11 with a solution of sodiumhydroxide. The batch is then made up to volume and filtered through asterilizing grade membrane filter into a sterile 10 ml glass vial andsealed with sterile closures and overseas.

Example 40

suppository

mg/suppository Active ingredient 250 Hard Fat, B.P. 1770 2020

One-fifth of the hard fat is melted in a steam-jacketed pan at 45° C.maximum. The active ingredient is sifted through a 200 μm sieve andadded to the molten base with mixing, using a high shear stirrer, untila smooth dispersion is achieved. Maintaining the mixture at 45° C., theremaining hard fat is added to the suspension and stirred to ensure ahomogenous mix. The entire suspension is passed through a 250 μmstainless steel screen and, with continuous stirring, is allowed to coolto 40° C. At a temperature of 38° C. to 40° C., 2.02 g of the mixture isfilled into suitable, 2 ml plastic molds. The suppositories are allowedto cool to room temperature.

Example 41

Antiviral Activity

All of the compounds of the preferred embodiments are novel and some arevaluable for their properties as non-toxic inhibitors of the primaryreplication of HIV-1 in previously uninfected T-lymphocytes over aprolonged period of time.

In vitro testing was conducted on several of the compounds of thisinvention to determine their inhibitory properties. The results areshown in Tables 1, 2 and 3. The concentrations reported are μg/ml in theincubation media which affect the susceptibility of a continuous line ofT-cells developed at the Lady Davis Institute for Medical Research(Montreal) by Dr. Mark A. Wainberg toward infection by HIV-1 following aprotocol similar to that of H. Mitsuya and S. Broder, “Inhibition of thein vitro infectivity and cytopathic effect of human T-lymphotropic virustype III/lymphadenopathy—associated virus (HTLV-III/LAV) by2′3′-dideoxynucleosides”, Proc. Natl. Acad. Sci. USA, 83, pp. 1911-15(1986). Protection of the cell line from infection was monitored bystaining with monoclonal antibodies against viral proteins in thestandard manner (Table 1). In all experiments, comparisons were madewith the drug AZT as the control. In order to confirm the results, thedrug effects were monitored by measuring reverse transcriptase (RT)activity in the U-937 line of human monocytic cells as assayed in theusual manner with tritiated thymidine triphosphate (TTP) (Table 2). Thedrug effects on cell viability as measured by the well-know cytolyticeffects of HIV-1 on the MT-4 cell line was evaluated in the acceptedmanner (Table 1).

Toxicity

No toxic effects were observed in the above tests.

TABLE 1 Inhibition of HIV-1 product by compounds of formula (I) in MT-4cells a) Viable cell counts (6 days in culture) using 2 μg/ml ofcompound Compound Cell Viability % no drug 6.47 AZT 88.6 cis-XI 87.4trans-XI 24 cis-XII(b) 14 cis-LVI 11 cis-LIII 18 cis-XVIII 14 b) P-24immunofluorescence Time in Culture % Immunofluorescent Cells (Days) NoDrug 2 μg/ml AZT 2 μg/ml cis-XI 3   5.9 1.0 1.0 6 99 1.0 7.6 c) Reversetranscriptase assay Time in Culture RT Activity (CPM × 1000)/ml (Days)No Drug 2 μg/ml AZT 2 μg/ml cis-XI 3  36.43 1.564 2.381 6 339.0 1.7482.301

TABLE 2 Inhibition of HIV-1 production by compounds of formula (I) inH-9 cells Reverse transcriptase assay Time in Culture RT Activity (CPM ×1000)/ml (Days) No Drug 2 μg/ml AZT 2 μg/ml cis-XI 5 9.117 3.346 3.077 8438.5 3.414 5.853 11 2550 2.918 3.560 14 2002 8.320 2.872 7 584.5 2.9972.399 21 365.2 3.111 2.907 25 436.4 15.88 4.020 29 92.38 32.08 3.756 33111.1 612.2 3.803 37 32.28 878.2 4.193 41 384.4 994.0 4.515 45 33.6432.91 3.441

TABLE 3 Inhibition of HIV-1 production by compounds of formula (I) inH-9 cells. RT activity (cpm) after: Inhibitor Conc.- 8 days 12 days 26days none — 198,612 327,570 239,019 trans-(XXXVI) 10 μM 4,608 83,462312,478 trans-(XXXVI) 50 μM 1,319 758 1,732 AZT 20 μM 633 419 821 none —64,769 119,580 227,471 cis-(XXXVIII) 20 μM 2,618 130,563 210,583cis-(XXXVIII) 50 μM 1,132 39,752 231,609 AZT 20 μM 587 1,316 679

What is claimed is:
 1. A compound selected from the group consisting of:cis-2-acetoxymethyl-4-(thymin-1′-yl)-1,3,-dioxolane;cis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane;cis-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane; andcis-2-hydroxymethyl-4-(cytosin-1′yl)-1,3-dioxolane.
 2. A compoundaccording to claim 1, wherein said compound is in the form of a singleoptical isomer or a mixture of optical isomers.
 3. A compound accordingto claim 1, wherein said compound iscis-2-acetoxymethyl-4-(thymin-1′-yl)-1,3-dioxolane.
 4. A compoundaccording to claim 1, wherein said compound is:cis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane.
 5. A compoundaccording to claim 1, wherein said compound iscis-2-benzoyloxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane.
 6. A compoundaccording to claim 1, wherein said compound iscis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane.
 7. A compoundaccording to claim 2, wherein said compound iscis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane.
 8. A compoundaccording to claim 7, wherein said compound is in the form of theracemic mixture.
 9. A compound according to claim 7, wherein saidcompound is in the form of a single optical isomer.
 10. A compoundaccording to claim 6, wherein said compound is:(d)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane.
 11. A compoundaccording to claim 6, wherein said compound is(l)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3dioxolane.
 12. A compoundaccording to claim 2, wherein said compound iscis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane.
 13. A compoundaccording to claim 12, wherein said compound is in the form of theracemic mixture.
 14. A compound according to claim 12, wherein saidcompound is in the form of a single optical isomer.
 15. A compoundaccording to claim 14, wherein said compound is(d)-cis-2-hydroxymethyl-4-(thymin-1′-yl)-1,3-dioxolane.
 16. A compoundaccording to claim 14, wherein said compound is(l)-cis-2-hydroxymethyl-4-(thymin-1-yl)-1,3-dioxolane.
 17. A method forthe treatment of an HIV infection, in a mammal, comprising administeringan effective amount of a compound according to claim 9 to a mammal inneed of such treatment.
 18. A method for the treatment of an HIVinfection, in a mammal, comprising administering an effective amount ofa compound according to claim 10 to a mammal in need of such treatment.19. A method for the treatment of an HIV infection, in a mammal,comprising C administering an effective amount of a compound accordingto claim 10 to a mammal in need of such treatment.
 20. A method for thetreatment of an HIV infection, in a mammal, comprising administering aneffective amount of a compound according to claim 11 to a mammal in needof such treatment.
 21. A method according to claim 17, wherein saidmammal is a human.
 22. A method according to claim 10, wherein saidmammal is a human.
 23. A method according to claim 19, wherein saidmammal is a human.
 24. A method according to claim 20, wherein saidmammal is a human.
 25. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound according to claim 1.26. A composition according to claim 25, wherein the amount of saidcompound is 10-1500 mg.
 27. A pharmaceutical composition according toclaim 26, wherein said compound iscis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane.
 28. Apharmaceutical composition according to claim 27, wherein said compoundis: (d)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3-dioxolane.
 29. Apharmaceutical composition according to claim 27, wherein said compoundis (l)-cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane.
 30. Apharmaceutical composition of claim 26, wherein the amount of saidcompound is 20-1000 mg.
 31. A pharmaceutical composition of claim 27,wherein the amount of said compound is 20-1000 mg.
 32. A pharmaceuticalcomposition of claim 28, wherein the amount of said compound is 20-1000mg.
 33. A pharmaceutical composition of claim 28, wherein the amount ofsaid compound is 20-1000 mg.
 34. A pharmaceutical composition of claim30, wherein the amount of the compound is 50-700 mg.
 35. Apharmaceutical composition of claim 31, wherein the amount of thecompound is 50-700 mg.
 36. A pharmaceutical composition of claim 32,wherein the amount of the compound is 50-700 mg.
 37. A pharmaceuticalcomposition of claim 33, wherein the amount of the compound is 50-700mg.
 38. A compound selected from the group consisting of:cis-2-benzoyloxymethyl-4-(cytosin-1′-yl),-1,3 dioxolane;cis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane; andpharmaceutically acceptable salts, pharmaceutically acceptable esters,and pharmaceutically acceptable salts of esters thereof.
 39. A compoundaccording to claim 38, wherein said compound iscis-2-hydroxymethyl-4-(cytosin-1′-yl)-1,3 dioxolane or apharmaceutically acceptable salt, pharmaceutically acceptable ester, orpharmaceutically acceptable salt of an ester thereof, in the form of aracemic mixture or a single optical isomer.